Pharmaceutical compositions comprising delayed-release gelling agent compositions

Abstract

To provide an immediate release solid oral dosage form comprising an active agent susceptible to abuse (e.g., an opioid analgesic), which is tamper-resistant.SOLUTION: A solid oral dosage form comprises an opioid analgesic composition in an immediate release form and a gelling agent composition in a delayed release form, wherein the solid oral dosage form is free of or substantially free of the opioid analgesic composition in an extended release form.SELECTED DRAWING: Figure 5

Description

[Technical Field]

[0001] The present invention relates to the field of tamper- and abuse-resistant pharmaceutical dosage forms. The present invention is directed to abuse-deterrent immediate release solid oral dosage forms, methods for their preparation and uses. do. [Background technology]

[0002] Pharmaceutical products can be subject to abuse. For example, certain doses of opioid painkillers can It may be more potent when administered parenterally compared to the same dose administered orally. Some formulations can be tampered with to facilitate unauthorized use of the opioids therein If the dosage form is prone to abuse and / or the abuser likes the high they get from abuse, Such abuse of opioid dosage forms may encourage abusers to take the dosage form again. A pattern of abuse can occur.

[0003] Reduce the abuse potential of immediate-release dosage forms containing drugs susceptible to abuse, such as opioid analgesics One form of abuse is parenteral or The drug contained therein is released for illicit use, such as by absorption through the outer mucosal surface. The crushed dosage form is mixed with a solution. and a viscosity that prevents the drug from being drawn into a needle, thereby hindering parenteral abuse. Similarly, when the crushed dosage form is applied to a mucosal surface (e.g., the nasal cavity), The substance forms a gel after contact with mucosal moisture, thereby preventing absorption.

[0004] One of the problems to be overcome when incorporating gelling agents into immediate release dosage forms is the need to prevent tampering. Such agents may be provided in immediate release dosage forms when included in an amount sufficient to prevent It has sustained release properties.

[0005] The art provides parenteral and nasal abuse-resistant drugs to combat abuse of opioid analgesics and the like. There is a need for an immediate release solid oral dosage form containing an active agent that is amenable to administration. The formulation, when properly administered, provides immediate release of the active agent, while still providing a level of protection that is susceptible to abuse. Tampering requires immediate release formulations containing gelling agents to maintain their abuse-deterrent properties. It is being done. Summary of the Invention

[0006] An object of certain embodiments of the present invention is to provide a tamper-resistant, abuse-prone device. To provide an immediate release solid oral dosage form containing an active agent (e.g., an opioid analgesic). do.

[0007] An object of certain embodiments of the present invention is to provide a dosage form that is less susceptible to parenteral abuse than other dosage forms. and (c) providing an immediate release solid oral dosage form containing an active agent (e.g., an opioid analgesic) susceptible to To do this.

[0008] An object of certain embodiments of the present invention is to provide a dosage form that is less susceptible to intranasal abuse than other dosage forms. and (c) providing an immediate release solid oral dosage form containing an active agent (e.g., an opioid analgesic) susceptible to To do this.

[0009] It is a further object of certain embodiments of the present invention to provide a dosage form that is less prone to diversion and abuse than other dosage forms. and (c) providing an immediate release solid oral dosage form containing an active agent (e.g., an opioid analgesic) susceptible to To do this.

[0010] It is a further object of certain embodiments of the present invention to provide an immediate release solid state drug as disclosed herein. The oral dosage form is administered to a patient in need thereof to treat a disease or condition in a human patient. or to treat a condition (e.g., pain).

[0011] It is a further object of certain embodiments of the present invention to provide a dosage form that: Methods of treating pain in human patients with immediate release solid oral dosage forms containing opioid analgesics The purpose is to provide

[0012] Another object of certain embodiments of the present invention is to provide a method for the production of abuse-resistant, By providing a method for preparing an oral dosage form of a pancreatic active drug (e.g., an opioid analgesic), be.

[0013] The above objectives and others can be achieved in certain embodiments by administering an immediate release active agent (e.g., an opioid inhibitor) to a patient. A solid oral dosage form comprising a sustained-release active agent (analgesic) composition and a delayed-release gelling agent composition. The present invention is directed to a solid oral dosage form that is free of, or substantially free of, a pharmaceutical composition. This can be achieved.

[0014] In some embodiments, the present invention provides an immediate release active agent (e.g., opioid analgesic) composition. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release active agent composition. and the delayed release gelling agent composition comprises a gelling agent and an enteric material. , the immediate-release active agent (e.g., opioid analgesic) composition and the delayed-release gelling agent composition. In some embodiments, the enteric material is soluble at a pH of 5.5 or greater and It is not soluble at a pH below 5.5.

[0015] In some embodiments, the intact (undamaged) solid oral dosage form is dissolved in water at room temperature. The viscosity of the solution obtained at 5 minutes in approximately 5 ml and the viscosity of the intact solid oral dosage form at room temperature is 0. The viscosity ratio of the solution obtained at 5 minutes in about 5 ml of 1N HCl is about 10:1 or more. .

[0016] In some embodiments, the opioid analgesic in the immediate release solid oral dosage forms disclosed herein is Each opioid analgesic particle may be in the form of one or more particles. (ii) an inert core coated with an iodine analgesic; or (iii) a matrix material containing It may contain dispersed opioid analgesics.

[0017] In some embodiments, the delayed release gelling agent composition in the immediate release solid oral dosage forms disclosed herein The composition may be in the form of one or more particles. Each delayed-release gelling agent particle comprises: (ii) a gelling agent coated with an enteric material; and an inert core overcoated with an enteric material, or (iii) an enteric matrix It may include a gelling agent dispersed in the material.

[0018] In some embodiments, the opioid analgesic in the immediate release solid oral dosage forms disclosed herein is , may be coated onto one or more delayed-release gelling agents particles. In some embodiments, one or more delayed-release gelling agents may be present in the immediate-release solid oral dosage forms disclosed herein. The drug particles are dispersed in a matrix (e.g., a matrix tablet) that contains an opioid analgesic. In another embodiment, one or more delayed-release gelling agent particles and one or more delayed-release gelling agent particles may be present. The immediate-release opioid particles or particles are contained within a pharmaceutically acceptable capsule.

[0019] In some embodiments, tampering of the immediate release solid oral dosage forms disclosed herein can occur by This gives the formulation a viscosity that makes it unsuitable for parenteral administration.

[0020] In some embodiments, crushed or whole solid oral dosage forms can be prepared without stirring at room temperature. Dissolve in 5 ml or 10 ml of solvent without stirring, and add the resulting solution to 18 Based on needle penetration testing by aspirating with a 22, 25, or 27 gauge needle The recovery of opioid analgesic from the immediate release solid oral dosage forms disclosed herein is about 40%. Less than, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4% less than or about 2%.

[0021] Another object, in certain embodiments, is to (i) prepare a delayed-release gelling agent composition. (ii) blending the delayed-release gelling agent composition with an active agent (e.g., an opioid analgesic); and (iii) compressing the blend into tablets to prepare a solid oral dosage form. This can be achieved by the present invention, which is directed to a process for

[0022] In some embodiments, the process for preparing the immediate release solid oral dosage forms disclosed herein comprises: Rotor powder stratification, fluid bed granulation, roller compaction, fluid bed coating (Wurster Coating) and combinations thereof. This includes enteric coating.

[0023] In some embodiments, the process for preparing the immediate release solid oral dosage forms disclosed herein comprises: The method includes (i) preparing one or more delayed-release gelling agent particles; and (ii) preparing one or more delayed-release gelling agent particles. Alternatively, the method may comprise coating a plurality of delayed-release gelling agent particles with an opioid analgesic. wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and is free or substantially free of sustained-release opioid analgesic compositions. In some embodiments, the process for preparing the immediate release solid oral dosage forms disclosed herein may include one or more The present invention relates to a pharmaceutical composition comprising a plurality of delayed-release gelling agent particles and one or more immediate-release opioid particles. This may include placing it in an acceptable capsule.

[0024] In some embodiments, the process for preparing the immediate release solid oral dosage forms disclosed herein comprises: The process includes (i) preparing one or more particles; (ii) forming one or more particles; (iii) coating the composition with an opioid analgesic composition; and and blending one or more particles coated with the delayed-release gelling agent composition. wherein the solid oral dosage form comprises an immediate-release opioid analgesic composition; and The solid oral dosage form is free or substantially free of a sustained-release opioid analgesic composition. .

[0025] In some embodiments, the process for preparing the immediate release solid oral dosage forms disclosed herein comprises: The method comprises (i) preparing one or more delayed-release gelling agent particles; and (ii) administering the opioid to the patient. a matrix containing an iodine analgesic composition and one or more delayed-release gelling agent particles dispersed therein; wherein the solid oral dosage form comprises an immediate-release opioid analgesic composition. and the solid oral dosage form is free of, or substantially free of, a sustained-release opioid analgesic composition. Not at all.

[0026] In a further embodiment, the present invention provides a method for administering to a patient in need thereof a method as disclosed herein. and administering an immediate release solid oral dosage form of This article covers how to do this.

[0027] The above and other features of the present disclosure, their nature and various advantages, are best understood from the following detailed description taken in conjunction with the accompanying drawings. This will become even clearer when you consider the following detailed explanation: [Brief explanation of the drawings]

[0028] [Figure 1] 1 shows a process flow diagram for producing solid oral dosage forms according to non-limiting embodiments disclosed herein, including rotor-layered and enteric-coated pellets. [Figure 2] 1 shows a process flow diagram for producing a solid oral dosage form according to a non-limiting embodiment disclosed herein, comprising top-sprayed granules. [Figure 3A] FIG. 1 shows a process flow diagram for producing a solid oral dosage form according to non-limiting embodiments disclosed herein, including roller-compacted and bottom-sprayed granulation. [Figure 3B] FIG. 1 shows a process flow diagram for producing a solid oral dosage form according to non-limiting embodiments disclosed herein, including roller-compacted and bottom-sprayed granulation. [Figure 4] 1 shows a chart showing the volume of active agent withdrawn after a needle passage test performed on intact tablets in tap water at room temperature (Example 8). [Figure 5] 1 shows a chart showing the volume of active agent withdrawn after needle penetration testing performed on crushed and intact tablets in tap water at room temperature (Example 8). [Figure 6] 1 shows a chart showing the assay percent of active drug aspirated after a needle passage test performed on intact tablets in tap water at room temperature (Example 8). [Figure 7] 1 shows a chart showing the assay percent of active agent aspirated after needle passage testing performed on crushed and intact tablets in tap water at room temperature (Example 8). [Figure 8] Table 4 in Example 2, Table 9 in Example 4, and Table 16 in Example 7 show dissolution profiles for the disclosed tablet formulations. [Figure 9] Tables 9 and 10 in Example 4 show dissolution profiles for the disclosed tablet formulations. [Figure 10] Tables 4 and 5 in Example 2 show the dissolution profiles for the disclosed tablet formulations. [Figure 11] Tables 16 and 17 in Example 7 show dissolution profiles for the disclosed tablet formulations. DETAILED DESCRIPTION OF THE INVENTION

[0029] In one aspect, the present invention provides an opioid analgesic composition in immediate release form and a gel in delayed release form. a solid oral dosage form comprising an opioid analgesic composition in sustained release form; The present invention is directed to such solid oral dosage forms that are free of, or substantially free of, hydroxybenzoates.

[0030] In certain embodiments, the opioid analgesic is morphine, hydromorphone, hydrocodone, or oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, di Hydromorphine, oxymorphone, fentanyl, buprenorphine, and its pharmaceutically acceptable a salt thereof, a solvate thereof, a prodrug thereof, and a mixture thereof. .

[0031] In one embodiment, the solid oral dosage form comprises a therapeutically effective amount of an opioid analgesic. In certain embodiments, the solid oral dosage form comprises an analgesically effective amount of an opioid analgesic. The solid oral dosage form contains from about 0.1% to about 80% (w / w) of an opioid analgesic, from about 0.5% to about 100% (w / w) of an opioid analgesic. It contains about 30% (w / w), or about 1% to about 10% (w / w).

[0032] In another embodiment, the method is carried out in 900 ml of 0.1 N HCl at room temperature using USP Apparatus As measured by in vitro dissolution in a 1000 ml (#40 mesh basket), The solid oral dosage form releases at least about 80% of the opioid analgesic within 30 minutes. Under certain circumstances, solid oral dosage forms may be prepared by soaking in 900 ml of 0.1 N HCl at room temperature in USP Measured by in vitro dissolution in Apparatus 1 (#40 mesh basket) When the solid oral dosage form of the present invention is administered, it releases at least about 85% of the opioid analgesic within 30 minutes. At least about 90%, or at least about 95% is released.

[0033] In another embodiment, the method is carried out in 900 ml of 0.1 N HCl at room temperature using USP Apparatus As measured by in vitro dissolution in a 1000 ml (#40 mesh basket), The solid oral dosage form releases at least about 80% of the opioid analgesic within 45 minutes. Under certain circumstances, solid oral dosage forms may be prepared by soaking in 900 ml of 0.1 N HCl at room temperature in USP Measured by in vitro dissolution in Apparatus 1 (#40 mesh basket) When the solid oral dosage form of the present invention is administered, it releases at least about 85% of the opioid analgesic within 45 minutes. At least about 90%, or at least about 95% is released.

[0034] In another embodiment, the method is carried out in 900 ml of 0.1 N HCl at room temperature using USP Apparatus As measured by in vitro dissolution in a 1000 ml (#40 mesh basket), The solid oral dosage form releases at least about 80% of the opioid analgesic within 60 minutes. Under certain circumstances, solid oral dosage forms may be prepared by soaking in 900 ml of 0.1 N HCl at room temperature in USP Measured by in vitro dissolution in Apparatus 1 (#40 mesh basket) When administered, the solid oral dosage forms of the present invention deliver at least about 85% of the opioid analgesic within 60 minutes. At least about 90%, or at least about 95% is released.

[0035] In one particular embodiment, the delayed release gelling agent composition in the solid oral dosage form of the present invention is a gellant. Gelling agents include, for example, starch, starch derivatives, carboxylates, hydroxybenzoates, and enteric substances. Sodium dimethylcellulose, methylcellulose, hydroxyethylcellulose, hydro Hydroxypropyl cellulose, hydroxypropyl methylcellulose, attapulgite, tonite, dextrin, alginate, carrageenan, tragacanth gum, arabic gum, guar gum, xanthan gum, pectin, gelatin, kaolin, cross-linked polyacrylic acid, polyvinylpyrrolidone, polyethylene oxide, or polyvinyl alcohol, or In particular, the gelling agent in the solid oral dosage form of the present invention may be polyethyleneoxy a polysaccharide, a mixture thereof, a cellulose gum ... An example shows that the gelling agent comprises a polymer. The polymer is a multi-layer structure in a neutral pH aqueous solution. It may contain sugars (e.g., microbial polysaccharides) and / or anionic polymers. An example is xanthan gum. Examples of anionic polymers are polyacrylic acid or carbomer. In one embodiment, the gelling agent in the solid oral dosage form of the present invention comprises a xanthan Includes gums and carbomer homopolymers.

[0036] In certain embodiments, the solid oral dosage forms of the present invention comprise from about 0.1% to about 50% of a gelling agent; It contains about 0.5% to about 20%, or about 1% to about 10% (w / w).

[0037] In certain embodiments, the present invention provides a method for preparing an intact solid oral dosage form containing about 0.5 mL of water at room temperature. The viscosity of the solution obtained after 5 minutes in a volume of 10 ml to 50 ml is approximately 50 cP or more, approximately 75 cP or more , about 100 cP or more, or about 125 cP or more, wherein the viscosity is measured by a rotational viscometer. In one embodiment, the tampered solid oral dosage form is The viscosity of the solution obtained from the dosage form in about 0.5 ml to about 10 ml of water at room temperature after 2 minutes is about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more, In another embodiment, the intact solid oral dosage form Viscosity of the solution obtained at 5 minutes in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature is less than about 50 cP, less than about 40 cP, less than about 30 cP, less than about 20 cP, less than about 10 cP less than about 5 cP, or less than about 2 cP, where the viscosity is measured by a rotational viscometer. In another embodiment, the tampered solid oral dosage form is immersed in 0.1 N HCl at room temperature. The viscosity of the solution obtained in about 0.5 ml to about 10 ml at the 5th minute is less than about 50 cP, about 4 less than 0 cP, less than about 30 cP, less than about 20 cP, less than about 10 cP, less than about 5 cP, or The viscosity is less than about 2 cP, where the viscosity is measured by a rotational viscometer. In this state, the intact solid oral dosage form is dissolved in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature. The viscosity of the solution obtained at 5 minutes in 1 liter of water was 0.05% at room temperature from a tamped solid oral dosage form. Approximately 30% of the viscosity of the solution obtained in 5 minutes in about 0.5 ml to about 10 ml of 1N HCl , within about 20%, about 10%, or about 5%, where the viscosity is measured by a rotational viscometer. It is determined.

[0038] In certain embodiments, the present invention provides a method for dissolving a solid oral dosage form from an intact solid oral dosage form in about 5 ml of water at room temperature. The viscosity of the solution obtained at 5 minutes in the solution and the viscosity of the solution obtained at 0.1NH at room temperature from the intact solid oral dosage form were The viscosity ratio of the solution obtained at 5 minutes in approximately 5 ml of Cl is approximately 10:1 or more, approximately 15:1 or more , about 20:1 or greater, about 25:1 or greater, or about 30:1 or greater, wherein the viscosity is A solid oral dosage form is provided, as measured by a viscometer.

[0039] In another embodiment, the present invention provides a pharmaceutical composition comprising an opioid analgesic composition in the form of one or more particles. Each opioid analgesic particle is coated on an inert core. Alternatively, each opioid analgesic particle may comprise a matrix-bound opioid analgesic. It contains an opioid analgesic dispersed in a steroid substance.

[0040] In another embodiment, the present invention provides a method for preparing a delayed-release gelling agent composition in the form of one or more particles. Each delayed-release gelling agent particle is, for example, (i) an enteric coating material; (ii) coated with a gelling agent and coated with an enteric material (iii) an inert core coated with a nanoparticle; or (iv) a nanoparticle dispersed in a matrix material. Contains a gelling agent.

[0041] One embodiment of the present invention comprises one or more opioid analgesic particles and one or more Solid oral dosage form containing delayed-release gelling agent particles contained within a pharmaceutically acceptable capsule In one example, one or more opioid analgesic particles and one or more delay The extended-release gelling agent particles are compressed into a tablet.

[0042] One embodiment of the present invention is a method for administering an opioid analgesic composition comprising administering to a subject a subject the opioid analgesic composition comprising administering to a subject a subject a drug product comprising administering to ... In another embodiment, the solid oral dosage form comprises one or more particles coated thereon. The delayed-release gelling agent particles or particles are dispersed in a matrix containing an opioid analgesic composition. It's scattered.

[0043] In another embodiment of the solid oral dosage form of the present invention, the delayed release gelling agent composition comprises a gelling agent and The enteric coating may comprise an enteric material, wherein the enteric material dissolves at a pH above about 5.5. It does not dissolve at a pH below about 5.5; for example, enteric materials dissolve at a pH above about 5.5, and and that it does not dissolve at a pH below about 5.5.

[0044] Enteric materials according to the present invention include cellulosic materials, acrylic acid polymers, polymethacrylates, and the like. For example, enteric materials include methacrylic acid / methacrylic acid copolymers, and mixtures thereof. Methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate copolymer ethylene / methyl methacrylate copolymer, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydro Dimethylcellulose Trimellitate, Cellulose Acetate Phthalate, Polyvinyl Acetate acetate phthalate, or mixtures thereof.

[0045] When the delayed-release gelling agent composition is in the form of one or more particles, each particle may contain an enteric coating. Quality: about 10% to about 30% (w / w), about 12% to about 25% (w / w), about 0.1% to about 50 % (w / w), about 1% to about 20% (w / w), or about 2% to about 15% (w / w) obtain.

[0046] In certain embodiments, the present invention provides a solid oral dosage form further comprising an aversive agent. The agonist may be, for example, an emetic, an antagonist, a bittering agent, an irritant, or a mixture thereof. Emetics include, for example, methylcephalin, cephalin, emetine hydrochloride, psychotrin, and -Methylpsychotrin, emethamine, ipecamine, hydroipecamine, toconic acid (ipe cacunhic acid), ipecac, or a mixture thereof.

[0047] Antagonists that can be used in the present invention include naltrexone, naloxone, na Lumefene, cyclazacine, levallorphan, their pharmaceutically acceptable salts, and their solvates , their prodrugs, and combinations thereof.

[0048] Bittering agents that can be used include flavor oils, flavoring fragrances, oleoresins, plant extracts, leaf extracts, and the like. Extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinone sulfate In one embodiment, the aversive agent may be a benzoate, denatonium benzoate, or a mixture thereof. Spearmint oil, peppermint oil, eucalyptus oil, nutmeg oil, allspice, mayonnaise The bittering agent is selected from the group consisting of citric acid, bitter almond oil, menthol, and mixtures thereof. In an embodiment, the bittering agent is selected from the group consisting of lemon, orange, lime, grapefruit. Extracted from selected fruits and mixtures thereof.

[0049] Irritants that can be used as aversive agents include surfactants, capsaicin, capsaicin, For example, capsaicin analogs include resiniferol, capsaicin analogs, and mixtures thereof. Ceratoxin, tiniatoxin, heptanoyl isobutyramide, heptanoyl guaiacin amide, isobutyramide, guaiacylamide, dihydrocapsaicin, homovanillyl The surfactant may be octyl ester, nonanoyl vanillyl amide, or a mixture thereof. The active ingredients are poloxamer, sorbitan monoester, glyceryl monooleate, and lauryl sodium sulfate, or a combination thereof.

[0050] In certain embodiments, the solid oral dosage forms of the present invention contain from about 0.1% to about 30% (w / w) of a stimulant. / w), or about 0.5% to about 20% (w / w), or about 1% to about 10% (w / w) Contains.

[0051] Certain embodiments of the present invention provide a solid oral dosage form further comprising a pharmaceutically acceptable excipient. Such pharmaceutically acceptable additives include, for example, plasticizers, colorants, lubricants, agents, bulking agents, thermal lubricants, antioxidants, buffers, disintegrants, binders, diluents, fluidization promoters, anti- Adhesives, sweeteners, chelating agents, flavoring agents, surfactants, solubilizers, stabilizers, hydrophilic polymers mers, hydrophobic polymers, waxes, lipophilic substances, absorption enhancers, preservatives, absorbents, cross-linking agents, bio adhesive polymer, pore former, osmolality adjuster, polycarboxylic acid or combination thereof. The pharmaceutically acceptable excipient may comprise from about 0.1% to about 99% (w / w) of the solid oral dosage form. ), or about 10% to about 80% (w / w), or about 15% to about 70% (w / w) possible.

[0052] Bulking agents according to the present invention include, for example, lactose, dextrose, mannitol, microcrystalline In one embodiment, the fluidization enhancer is silicon dioxide. Another embodiment indicates that the lubricant comprises magnesium stearate. show.

[0053] The solid oral dosage form of certain embodiments of the present invention is rotor-layered and enteric-coated. sprayed pellets, top sprayed granules, roller compacted pellets, bottom sprayed delayed release gels comprising one or more of: The composition contains a curing agent.

[0054] The solid oral dosage forms of the present invention may be packaged in unit dosage form or in pharmaceutically acceptable capsules. The solid oral dosage form may also be in the form of a tablet. That's fine.

[0055] In certain embodiments of the present invention, the combination of an opioid analgesic and a gelling agent in a solid oral dosage form is The weight ratio is about 1:30 to about 30:1, or about 1:15 to about 15:1, or about 1:10 up to about 10:1, or about 1:8 to about 8:1, or about 1:5 to about 5:1, or about 1:3 to about 3:1, or about 1:1.5 to about 1.5:1.

[0056] In another embodiment of the present invention, the solid oral dosage form comprises a gelling agent and an enteric material, wherein The weight ratio of the gelling agent to the enteric substance is about 1:30 to about 30:1, or about 1:15 to about 1: 5:1, or about 1:10 to about 10:1, or about 1:8 to about 8:1, or about 1:3 It is about 3:1, or about 1:1.5 to about 1.5:1.

[0057] Dissolving the intact solid oral dosage form of the present invention in 5 ml of solvent with stirring at room temperature; and A needle penetration test was performed in which the resulting solution was aspirated through an 18-, 22-, 25-, or 27-gauge needle. In certain embodiments of the present invention, the recovery of the opioid analgesic is about 4 Less than 0%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4 %, or less than about 2%. Another embodiment is an intact solid oral dosage form of the present invention. was dissolved in 5 ml of solvent at room temperature without stirring, and the resulting solution was diluted with 18, 22, 25, or In a needle passage test using a 27-gauge needle, the recovery rate of opioid analgesics was , less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6% , less than about 4%, or less than about 2%.

[0058] In another embodiment of the present invention, the intact solid oral dosage forms of the present invention are mixed at room temperature with stirring. Dissolve in 10 ml of solvent, and pipette the resulting solution through an 18, 22, 25, or 27 gauge pipette. When subjected to needle passage testing, the recovery rate for opioid analgesics is approximately 40%. Less than, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4% In another embodiment, the intact solid oral dosage form of the present invention is Dissolve in 10 ml of solvent at room temperature without stirring, and use the resulting solution at 18, 22, 25, or After needle passage testing using a 27-gauge needle, the recovery rate of opioid analgesics is approximately Less than 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, about This indicates less than 4% or less than about 2%.

[0059] In certain embodiments of the present invention, the crushed solid oral dosage form is mixed with solvent 5 at room temperature while stirring. ml, and the resulting solution was drawn up with an 18, 22, 25, or 27 gauge needle. In needle passage tests, the recovery rate of opioid analgesics was less than approximately 40% and less than approximately 30%. Full, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or about 2% Indicates that it is less than.

[0060] Another embodiment of the present invention is to add the crushed solid oral dosage form to 10 ml of solvent while stirring at room temperature. and aspirate the resulting solution into an 18, 22, 25, or 27 gauge syringe needle. In needle passage tests, the recovery rates of opioid analgesics were less than approximately 40%, less than approximately 30%, and Less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% Indicates that.

[0061] A further embodiment of the present invention is to dissolve the crushed solid oral dosage form in 5 ml of solvent at room temperature without stirring. and aspirate the resulting solution into an 18, 22, 25, or 27 gauge syringe needle. In needle passage tests, the recovery rates of opioid analgesics were less than approximately 40%, less than approximately 30%, and Less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% This indicates that

[0062] In another embodiment of the present invention, the crushed solid oral dosage form is dissolved in 10 ml of solvent without stirring at room temperature. Dissolve in 1 ml of water and aspirate the resulting solution with an 18, 22, 25, or 27 gauge needle. In needle passage tests, the recovery rate of opioid analgesics was less than approximately 40% and less than approximately 30%. , less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2% Indicates that the battery is full.

[0063] In certain embodiments of the present invention, the viscosity of the solid oral dosage form is from about 0.5 ml to about 10 ml of water. When mixed with 1, it renders the opioid analgesic unsuitable for parenteral administration. In this embodiment, the viscosity of the solid oral dosage form of the present invention when mixed with about 0.5 ml to about 10 ml of water is Opioid analgesics are unsuitable for intravenous administration.

[0064] In certain embodiments of the solid oral dosage form of the present invention, the delayed release gelling agent composition comprises a delayed release gelling agent. About 5% to about 35% (w / w) of enteric material, or about 5% of the total weight of the gelling agent composition up to about 15% (w / w), or about 15% to about 25% (w / w), or about 25% to about 35% % (w / w) of rotor-stratified and enteric-coated pellets. Examples include rotor-layered and enteric-coated pellets of delayed release gelling agent compositions. It is shown to contain about 10% (w / w) of the enteric coating based on the total weight. The rotor-layered and enteric-coated pellets are mixed to form a delayed-release gelling agent composition having a total weight of 1000g. The enteric coating is shown to contain approximately 30% (w / w) of the total.

[0065] The present invention also provides a solid oral dosage form comprising a delayed release gelling agent composition, the solid oral dosage form comprising a top spray granules, wherein about 90% to about 1% of the top spray granules incorporated into the solid oral dosage form 00% (specifically, about 95% to about 100%; or more specifically, about 99% to about 100 %) is one or more of a 100 mesh screen, a 200 mesh screen, and a pan. The present invention relates to a solid oral dosage form, wherein the solid oral dosage form is maintained in a state where the amount of the solid oral dosage form is less than 100%.

[0066] In another embodiment, the present invention provides a solid oral dosage form comprising a delayed release gelling agent composition, and a top spray granule, wherein the top spray granule is incorporated into a solid oral dosage form. Approximately 20% to 50% (specifically, approximately 30% to 45%) is screened on a 100 mesh screen. In one embodiment, the solid oral dosage form is provided with a hydroxybenzoate or hydroxybenzoate. The above shows that about 40% of the spray granules are retained on a 100 mesh screen. It relates to solid oral dosage forms.

[0067] In certain embodiments, the present invention is a solid oral dosage form comprising a delayed-release gelling agent composition. and a top spray granule, wherein the top spray is incorporated into a solid oral dosage form. Approximately 20% to 50% of the granules (specifically, approximately 30% to 45%) are filtered through a 200 mesh screen. In one embodiment, the solid oral dosage form is held in a sphere. Approximately 40% of the top spray granules are retained on the 200 mesh screen. .

[0068] Another embodiment of the present invention is a solid oral dosage form in which the delayed release gelling agent composition is a top-spray gelling agent. The solid oral dosage form contains about 10% to 10% of the top spray granules. Approximately 30% (or approximately 15% to approximately 25%) is sieved through a 200 mesh screen. In one example, approximately 100% of the top spray granules incorporated into a solid oral dosage form are retained. 20% is retained after sieving through a 200 mesh screen.

[0069] The delayed release gelling agent composition in the solid oral dosage form of the present invention is present in an amount of from about 0.4 g / ml to about 0.6 g The present invention may comprise roller compacted pellets having a bulk density in the range of 1000 / ml. The compressed pellets have a tap density ranging from about 0.55 g / ml to about 0.65 g / ml. good.

[0070] The solid oral dosage form of the present invention may be in the form of a compressed tablet. The present invention relates to compressed tablets having a hardness of from about 5 Kp to about 18 Kp.

[0071] In certain embodiments, the solid oral dosage forms of the present invention can be stored in water for a period of about 10 seconds to about 30 minutes. or has a disintegration time in water in the range of about 1 minute to about 10 minutes, or It has a disintegration time in water ranging from about 10 seconds to about 2 minutes.

[0072] In other embodiments, the solid oral dosage forms of the present invention are simmered in SGF for about 10 seconds to about 30 minutes, or It has a disintegration time ranging from about 1 minute to about 10 minutes, or from about 10 seconds to about 2 minutes.

[0073] Another aspect of the present invention is an opioid analgesic composition in immediate release form and a gel in delayed release form. The present invention provides a solid oral dosage form comprising a gelling agent composition comprising a gelling agent and a gelling agent. The enteric coating material is then dissolved in 900 ml of 0.1N HCl at room temperature. by in vitro lysis in a P Apparatus 1 (#40 mesh basket) When measured, the solid oral dosage form releases at least about 85% of the opioid analgesic within 45 minutes. Put out.

[0074] A further aspect of the present invention is the provision of an opioid analgesic composition in immediate release form and in delayed release form. 1. A solid oral dosage form comprising a gelling agent composition, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. first, the gelling agent composition comprises a gelling agent and an enteric material; and The enteric material dissolves at a pH greater than about 5.5 and does not dissolve at a pH less than about 5.5. It relates to solid oral dosage forms.

[0075] The present invention also provides an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form. 1. A solid oral dosage form comprising a composition comprising: The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. first, The gelling agent composition contains about 10% (w / w) of enteric material based on the total weight of the pellet. and Dissolve the intact solid oral dosage form in approximately 5 ml to approximately 10 ml of tap water at room temperature without stirring. and aspirating the resulting solution with an 18, 22, 25, or 27 gauge needle. said solid has a recovery rate of less than about 15% of the opioid analgesic based on a needle passage test. Concerning oral dosage forms.

[0076] Another aspect of the present invention is an opioid analgesic composition in immediate release form and a gel in delayed release form. 1. A solid oral dosage form comprising an agent composition, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, The gelling agent composition contains about 10% (w / w) of enteric material based on the total weight of the pellet. and The intact solid oral dosage form is dissolved in approximately 5 ml to approximately 10 ml of tap water while stirring at room temperature. and aspirating the resulting solution with an 18, 22, 25, or 27 gauge needle. The solid has a recovery rate of less than about 5% of the opioid analgesic based on a needle passage test. An oral dosage form is provided.

[0077] The present invention further provides an opioid analgesic composition in immediate release form and a gelling agent in delayed release form. 1. A solid oral dosage form comprising the composition, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, The gelling agent composition contains about 30% (w / w) of enteric material based on the total weight of the pellet. and Add the intact solid oral dosage form to approximately 10 ml of tap water with or without stirring at room temperature. and aspirate the resulting solution into an 18, 22, 25, or 27 gauge syringe needle. Based on needle-passage testing, opioid analgesics have a recovery rate of less than approximately 20%. , including said solid oral dosage forms.

[0078] The present invention further provides an opioid analgesic composition in immediate release form and a gelling agent in delayed release form. 1. A solid oral dosage form comprising the composition, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, The gelling agent composition contains about 30% (w / w) of enteric material based on the total weight of the pellet. and The intact solid oral dosage form was dissolved in approximately 5 ml of tap water at room temperature without stirring, and the resulting Needle passage by aspirating the solution through an 18, 22, 25, or 27 gauge needle Based on testing, the solid oral dosage form has an opioid analgesic recovery rate of less than about 10%. do.

[0079] Yet another aspect of the present invention is an opioid analgesic composition in immediate release form and a delayed release form. 1. A solid oral dosage form comprising a gelling agent composition according to claim 1, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, The gelling agent composition contains about 30% (w / w) of enteric material based on the total weight of the pellet. and The intact solid oral dosage form was dissolved in approximately 5 ml of tap water with stirring at room temperature, and the resulting Needle penetration by withdrawing the solution into an 18, 22, 25, or 27 gauge needle and providing said solid oral dosage form, wherein the recovery rate of the opioid analgesic is less than about 5% based on a test. Provide.

[0080] In a further aspect, the present invention provides an opioid analgesic composition in immediate release form and a delayed release form. 1. A solid oral dosage form comprising a gelling agent composition according to claim 1, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, the gelling agent composition comprises top spray granules; and Add the intact solid oral dosage form to approximately 5 ml of tap water at room temperature with or without stirring. Dissolve in approximately 10 ml and insert the resulting solution into an 18, 22, 25, or 27 gauge syringe. Based on needle-passage testing, the recovery rate for opioid analgesics is approximately 2%. The solid oral dosage form is

[0081] In another aspect, the present invention provides an opioid analgesic composition in immediate release form and a delayed release form. 1. A solid oral dosage form comprising a gelling agent composition according to claim 1, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, the gelling agent composition comprises roller-compacted and bottom-sprayed granules; Add the intact solid oral dosage form to approximately 5 ml of tap water at room temperature with or without stirring. Dissolve in approximately 10 ml and insert the resulting solution into an 18, 22, 25, or 27 gauge syringe. Recovery rate of opioid analgesics is approximately 40% based on needle passage testing using needle aspiration. less than about 30%, less than about 10%, or less than about 8% do.

[0082] A further aspect of the present invention is the provision of an opioid analgesic composition in immediate release form and in delayed release form. 1. A solid oral dosage form comprising a gelling agent composition, The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, The gelling agent composition contains about 30% (w / w) of enteric material based on the total weight of the pellet. and The crushed solid oral dosage form is dissolved in approximately 10 ml of tap water with or without stirring at room temperature. Allow to dissolve and aspirate the resulting solution into an 18, 22, 25, or 27 gauge needle. Based on needle passage tests, the recovery rate of opioid analgesics is less than approximately 15% and approximately 10%. %, or less than about 5% of said solid oral dosage form.

[0083] The present invention also provides an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form. 1. A solid oral dosage form comprising a composition comprising: The solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. figure, the gelling agent composition comprises roller-compacted and bottom-sprayed granules; and The crushed solid oral dosage form is dissolved in approximately 10 ml of tap water with or without stirring at room temperature. Allow to dissolve and aspirate the resulting solution into an 18, 22, 25, or 27 gauge needle. Based on needle passage tests, the recovery rate of opioid analgesics is less than approximately 30% and approximately 25%. %, or less than about 5% of said solid oral dosage form.

[0084] The solid oral dosage forms of the present invention, in one particular embodiment, comprise an immediate release form of the active agent composition. and a gelling agent composition in a delayed release form, wherein the solid oral dosage form contains an active ingredient in the sustained release form. The active agent is free of, or substantially free of, an opioid agonist. , tranquilizers, CNS depressants, CNS stimulants, sedative-hypnotics, and mixtures thereof The drug may be selected from the group consisting of:

[0085] The present invention also provides a method for treating a disease or condition by administering a solid oral dosage form of the present invention. In certain embodiments, the solid oral dosage form is for use in the treatment of pain. It is suitable for

[0086] The present invention also provides a process for preparing a solid oral dosage form as discussed above, comprising: (i) preparing a delayed-release gelling agent composition; (ii) activating the delayed-release gelling agent composition; (iii) blending the blend into a tablet, In one embodiment, the preparing step comprises the step of: Layering, fluid bed granulation, roller compaction, fluid bed coating, and combinations thereof The enteric coating of the gelling agent may be carried out by a method including

[0087] The solid oral dosage forms of the present invention can also be prepared by (i) preparing one or more particles; (ii) coating one or more particles with an opioid analgesic composition; and (iii) ) forming a delayed-release gel of one or more particles coated with an opioid analgesic composition; The composition may be prepared by a process comprising blending the solid The oral dosage form comprises an opioid analgesic composition in immediate release form, and the solid oral dosage form comprises a sustained release form. free of, or substantially free of, opioid analgesic compositions in release form. The process further includes (iv) compressing the blend into tablets.

[0088] The solid oral dosage forms of the present invention also comprise: (i) one or more delayed-release gelling agent composition particles; and (ii) dissolving one or more delayed-release gelling agent particles in an opioid analgesic. The composition may be prepared by a process comprising coating the composition with a solid The solid oral dosage form contains an opioid analgesic in immediate release form, and the solid oral dosage form contains an opioid analgesic in sustained release form. An example is a process for producing an opioid analgesic composition that is free of, or substantially free of, an opioid analgesic composition in the form of and (iii) compressing the one or more coated particles into a tablet. Indicates that the group contains

[0089] Additionally, the present invention provides a method for preparing one or more delayed-release gelling agent particles; and (ii) a matrix comprising an opioid analgesic composition and one or more delayed-release gelling agent particles. and dispersing the solid oral dosage form in an immediate release form of the opioid. and the solid oral dosage form comprises an opioid analgesic composition in sustained release form. and a process for preparing the solid oral dosage forms discussed above that are free or substantially free of do.

[0090] definition As used herein, the singular forms "a," "an," and "the" are used unless the context requires otherwise. Unless otherwise specified, multiple referents are included. Thus, for example, "one abuse" Reference to a "susceptible active agent" includes a single active agent as well as two or more different active agents. A reference to a "gelling agent" includes a single gelling agent as well as a mixture of two gelling agents. Mixtures of the above different gelling agents are also included, and so forth.

[0091] As used herein, the term "about" in reference to a measured quantity means that the measurement is made and the subject of the measurement is known. as would be expected by one skilled in the art using a level of care appropriate to the accuracy of the object and measuring equipment. In certain embodiments, the term "about" refers to a normal variation in the quantity measured. includes ±10% of the recited number, such that "about 10" would include 9 to 11.

[0092] The terms "abuse-deterrent" and "tamper-resistant" refer to, for example, the ability to crush, chew, or otherwise alter the dosage form. by crushing, cutting, grating or grinding, or by dissolving in a common solvent (e.g., water, simulated biological media, Extraction of the opioid from the dosage form using alcohol or organic solvents, or any of At least some physical and / or chemical resistance, such as deterrence or resistance to combinations of Refers to a dosage form that provides a barrier to abuse, reduces abuse, or prevents abuse. The dosage form may include an agonist / antagonist combination that reverses the euphoria associated with Although they may not completely prevent abuse, they may deter or be resistant to abuse. is possible.

[0093] The term "recovery rate" refers to the percentage of a tubule that can be aspirated with a needle, e.g., a 27-gauge needle. The solution obtained in the pulverized dosage form (e.g., crushed and mixed in 5 mL of solvent) This refers to the amount of drug administered.

[0094] As used herein, the terms "active agent," "active ingredient," "pharmaceutical product," and "drug" are used interchangeably. The term "any entity" means any entity, whether or not authorized for that purpose by any governmental authority. Refers to any substance intended to have a therapeutic, prophylactic, or other intended effect. These terms refer to specific agents in any form that is pharmaceutically active. All pharmaceutically active agents, all pharmaceutically acceptable salts thereof, and complexes thereof, stereoisomers thereof This includes isomers, crystalline forms, co-crystals, ethers, esters, hydrates, solvates, and mixtures thereof. can be.

[0095] As used herein, the term "therapeutically effective" means to produce a desired therapeutic result. This refers to the amount of drug needed to achieve a desired outcome, or the rate of drug administration.

[0096] As used herein, the term "prophylactically effective" means to produce a desired prophylactic result. This refers to the amount of drug needed to achieve a desired outcome, or the rate of drug administration.

[0097] As used herein, the term "antitussive amount" refers to an amount of cough suppressant that relieves, suppresses, or It refers to an amount of drug sufficient to reduce the frequency of side effects.

[0098] As used herein, the term "analgesically effective amount" refers to an amount sufficient to produce analgesia. Refers to the amount of drug.

[0099] As used herein, the term "stereoisomer" refers to a stereoisomer that is a mixture of two or more different forms of a compound, each of which is a different form of a stereoisomer. It is a general term for all isomers of individual molecules that differ only in their enantiomers. isomers of compounds with one or more chiral centers that are not mirror images of one another (dimers) asteomers).

[0100] The term "enantiomer" or "enantiomeric" refers to a substance superimposable on its mirror image. Enantiomers refer to molecules that cannot be separated and are therefore optically active, while enantiomers refer to molecules that are polarized. If the plane of light is rotated in one direction by a certain number of degrees, its mirror image will have its plane of polarization rotated by the same number of degrees, but Rotate in the opposite direction.

[0101] The term "chiral center" refers to a carbon atom to which four different groups are attached.

[0102] The term "racemic" refers to a mixture of enantiomers.

[0103] The term "resolution" refers to the process of separating or concentrating one of the two enantiomeric forms of a molecule. means to remove.

[0104] The term "patient" refers to a person who exhibits a clinical presentation of specific signs or symptoms that indicate the need for treatment. and taking preventative or prophylactic measures against the condition. a subject who has been diagnosed with a condition to be treated or to be treated (pharmacologically); It particularly refers to a human. The term "subject" includes the definition of the term "patient" and otherwise Healthy individuals are not excluded.

[0105] "Pharmaceutically acceptable salts" include, but are not limited to, hydrochloride, hydrobromide, sulfate, etc. Salts, inorganic acid salts such as phosphates; formates, acetates, trifluoroacetates, maleates, alcohols Organic acid salts such as tungstates; methanesulfonates, benzenesulfonates, p-toluenesulfonates sulfonates such as benzoates; alginates, aspartates, glutamates, etc. Amino acid salts; metal salts such as sodium salts, potassium salts, and cesium salts; calcium salts, magnesium salts Alkaline earth metal salts such as neodymium salts; and triethylamine salts, pyridine salts, and picoline salts , ethanolamine salt, triethanolamine salt, discyclohexylamine salt, N,N and organic amine salts such as '-dibenzylethylenediamine salt.

[0106] As used herein, the term "ppm" means "parts per million."

[0107] The term "compression" refers to the process by which a tablet or any other compressed dosage form is formed by blending the components of the formulation. and compressing the blend to form the dosage form. Refers to the tableting process.

[0108] The recitation of ranges of values ​​herein is intended to be a general guideline unless otherwise indicated herein. It is intended simply to serve as a shorthand way of individually referring to each individual value that falls within a range. It is intended that each individual value be All methods described herein are incorporated herein by reference. Unless otherwise indicated or clearly contradicted by the context, Any suitable order may be used. The use of examples or exemplary language (eg, "such as") merely refers to certain particular materials and methods. It is intended to clarify the law and not to imply a limitation on scope. No language herein refers to any unclaimed element as essential to the practice of the disclosed materials and methods. should not be construed as indicating

[0109] The term "condition" or "conditions" includes acute and chronic pain, pulmonary edema, cough, diarrhea, inflammation or inflammatory disease, etc., administered to a subject in an effective amount of an active agent (an opioid analgesic or can be treated or prevented by administering a compound (such as a pharmaceutically acceptable salt thereof) Refers to a medical condition that can cause

[0110] The terms "treatment of" and "treating" refer to the reduction in the severity of a condition, e.g., pain. In one embodiment, "treating" or "treatment of" includes pain It may include inhibiting episodes, for example reducing their overall frequency.

[0111] The terms "prevention of" and "preventing" refer to the avoidance of the onset of a condition, e.g., pain. include.

[0112] "Free of or substantially free of sustained-release opioid analgesic compositions" or "sustained-release opioid analgesic compositions" "free of or substantially free of sustained release active agent compositions" or "sustained release form of "Free of or substantially free of analgesic compositions containing analgesic drugs" or "Active ingredient in sustained release form" The term "free or substantially free of active pharmaceutical ingredients" refers to the active pharmaceutical ingredients in a solid oral dosage form. About 15% or less, about 10% or less, about 5% or less of the analgesic or active agent is in a sustained-release formulation. refers to a solid oral dosage form that releases a drug in a sustained release profile (wherein the sustained release profile is, for example, , in 900 ml of 0.1 N HCl at room temperature, using USP Apparatus 1 (#40 mesh) Released over a period of more than 4 hours as measured by in vitro dissolution in a powder basket (It can refer to the amount of active agent delivered.)

[0113] The term "sustained release" refers to a particular formulation, e.g., to obtain a once-daily or twice-daily dosage form. "Sustained release active agent composition," "sustained release The terms "active agent composition in sustained release form," "sustained release active agent," and "active agent in sustained release form" are used interchangeably herein. The terms are used interchangeably.

[0114] The terms "delayed release gelling agent composition" and "gelling agent composition in delayed release form" are used interchangeably. These terms refer to the gelling agent that is released after an event has occurred. The change may be due to the passage of time, a trigger such as a change in pH, or any other trigger as would be understood by one of skill in the art. This may be a comparable event.

[0115] The term "release" when used in reference to a gelling agent refers to the release of a gel that results in an increase in viscosity. This refers to at least partial release of the agent.

[0116] The term "immediate release" refers to the results of a test performed in 900 ml of 0.1 N HCl at room temperature, as determined by USP App As measured by in vitro lysis in aratus 1 (#40 mesh basket) At least 85% of the active agent at 5, 15, 30, 45 or 60 minutes , at least 90%, or at least 95% release.

[0117] The terms "immediate release active drug composition" and "active drug composition in immediate release form" are used interchangeably. It is used for the purpose.

[0118] "Immediate Release Opioid Analgesic Composition" and "Opioid Analgesic Composition in Immediate Release Form" The terms are used interchangeably.

[0119] The viscosity measurements disclosed herein are taken at a spindle number (e.g., For viscosities in the range of 100 to 160,000 cP, the number of spindles is 1 to 7. Viscometer (e.g., Brookfield Engineering, Middleborough o, Brookfield RV viscometer or equivalent available from Mass. USA) Viscosity measurements are listed in the August 1, 2017 edition. United States Pharmacopeia (USP) monographs for carbomer homopolymers such as -NF35) (incorporated herein by reference), or ratios as would be understood by one of ordinary skill in the art. It can be measured according to comparable methods.

[0120] As used herein, the needle penetration test uses 5 mL and 10 mL of tap water at room temperature. This relates to tablets that are tested for syringeability after dissolving in a liquid. Intact and crushed forms were tested. Suction was applied using 18, 22, 25, or 27 gauge. This is done in a repetitive process over a period of approximately 1 to 60 minutes using a syringe needle. The aspirated active agent content is noted and assayed.

[0121] Disintegration testing was performed according to the United States Pharmacopeia (USP) Disintegration Test Procedure as set forth in the official April 1, 2006 edition. (incorporated herein by reference) in 0.1 N HCl and in water. The present invention relates to tablets that are tested for the active agent contained therein.

[0122] For purposes of this invention, "USP Apparatus 1 (#40 mesh basket)" refers to In vitro dissolution test of "USP Apparatus 1 basket, basket The test dosage form is fitted with a retaining spring that is placed on top of the dissolution medium. When hydrated, it reduces its tendency to adhere to the solid backing of the top of the basket or the bottom of the shaft. It is used in a slightly modified form by applying a passivated A stainless steel 316 spring, 1.5 cm outside diameter and 2 cm long, can be used.

[0123] Dosage form According to various embodiments, the present disclosure provides an immediate release opioid analgesic composition and a delayed release gel. In certain embodiments, the dosage form is directed to an immediate release solid oral dosage form comprising a stimulating agent composition. When administered orally intact as indicated, the delayed release gelling composition provides a In certain embodiments, the delayed release gelling composition, the opioid The analgesic, the antihistamine, or both may be in the form of one or more particles. In embodiments, the delayed release gelling composition is in a matrix material that includes an opioid analgesic. In other embodiments, the opioid inhibitor may be in the form of one or more dispersed particles. The pain relief composition comprises one or more gelling agents dispersed in a matrix material comprising a delayed release gelling agent composition. In certain embodiments, different types of particles may be present in the matrix. The delayed release gelling composition may comprise one or more particles dispersed in the gelling agent. and the opioid analgesic composition may be in the form of one or more particles. In other embodiments, the delayed release gelling composition may comprise one or more particles. and the opioid analgesic composition may be in the form of one or more delayed release gelling agents. The agent particles may be coated with the agent.

[0124] In certain embodiments where the active agent composition is in the form of one or more particles, the active agent The agent (e.g., opioid analgesic) composition is coated onto an inert particle or bead core. The active agent may be coated onto the surface of the particles to form a layer of the active agent on each particle in the dosage form. In this embodiment, instead of an inert particle or bead core, the particle core is a delayed release gelling agent composition. The active agent may be formed from a steroid, an aversive agent, an additive, or any combination thereof. It may be present in any one or more of the layers of the multiparticulate.

[0125] In certain embodiments, one or more opioid analgesic particles and one or more The delayed release gelling agent particles may be compressed into a tablet or placed in a pharmaceutically acceptable capsule. It may be housed inside.

[0126] One or more aversive agents may be included in the dosage form. For example, the aversive agent may be one or more may be contained in a plurality of particles, which may be combined with the delayed release gelling agent composition and the active agent composition. In other embodiments, one or more aversive agents may be combined into a dosage form comprising a delayed release The gelling agent may be present in the gelling agent composition, or in combination with the active agent composition, or in combination with both compositions. That's fine.

[0127] According to certain embodiments, the immediate release solid oral dosage form is a dosage form as intended. When ingested, the active agent may be released according to an immediate release dissolution profile. While the dosage form may be, for example, dissolved in water (or any other aqueous solution with a pH above 5.5) Delayed release when tampered with by mixing in about 0.5 ml to about 10 ml The gelling agent composition may be at least partially released to increase the viscosity of the tampered dosage form. and administering the active agent (e.g., opioid analgesic) composition parenterally (e.g., intravenously). It is deemed inappropriate.

[0128] The immediate release profile can be modified by, for example, modifying the matrix material, adding additives, etc. Changing the type and amount of aversive agents added, changing the type and amount of additional ingredients By changing the formulation of the dosage form by including For example, organic or inorganic materials that can function as pore formers can be used. and contains substances that can be dissolved, extracted, or leached from the dosage form in the environment of use. The immediate release profile can be affected by including a release modifier that may be present. Pore-forming agents include hydroxypropyl methylcellulose, lactose, and the above-mentioned The hydrophilic material may include one or more hydrophilic materials such as any mixture of

[0129] In certain embodiments, the dosage form (e.g., matrix form) may be, but is not limited to, However, digestible long chain (C8-C 50 , especially C 12 ~C 40 ) substituted or unsubstituted hydrocarbons, e.g. For example, natural or synthetic waxes (such as beeswax, glycowax, castor wax, and carnauba wax) Hydrophobic substances containing fatty alcohols (lauryl, myristyl, stearyl, cetyl, etc.) or preferably cetostearyl alcohol), including but not limited to fatty acid esters. Fatty acids, including esters, fatty acid glycerides (mono-, di-, and triglycerides), hydrogenated Fats, hydrocarbons, normal waxes, stearic acid, stearic acid It may include allyl alcohol and hydrophobic and hydrophilic substances with a hydrocarbon backbone.

[0130] In addition to the above ingredients, the dosage form may also contain appropriate amounts of other pharmaceutically acceptable excipients, such as: Diluents, lubricants, binders, granulation aids, and glidants known to those skilled in the art may be included.

[0131] According to various embodiments, the immediate release solid oral dosage form (e.g., compressed tablet) has a saturation of about 2 Kp to about 100 Kp. It may have a hardness of about 20 Kp, or from about 5 Kp to about 18 Kp.

[0132] In a further embodiment, the immediate release solid oral dosage form is in any suitable form for administration. Dosage forms include compressed tablets, gelcaps, capsules, caplets, granules, and lozenges. It may be in the form of a capsule, bulk powder, film, or extruded form. Tablets are not limited to these. The capsule may have any suitable shape, including, but not limited to, a round, caplet, or lozenge shape. obtain.

[0133] For example, a formulation containing an active agent composition and a delayed-release gelling agent composition as well as any additional ingredients. The whole form may be in the form of a unit dosage form such as a tablet. The tablet may be prepared by compression, such as a compressed tablet. The tablet core may contain one or more additives and / or aversive agents. The tablet core may also contain an active agent composition dispersed therein. The multiparticulates may be formed as follows:

[0134] In other embodiments, any additional components in addition to the active agent composition and delayed-release gelling agent composition may be used. The entire dosage form, including the ingredients, may be in the form of multiple particles. It may be contained in any pharmaceutically acceptable capsule.

[0135] When the dosage form is in the form of a tablet, such tablet may be compressed, crushed, or the like. may be sugar-coated or film-coated , may be compressed multiple times, or may be multi-layered.

[0136] When the dosage form is a multiparticulate formulation, the unit dose of the multiparticulate dosage form of the present invention may be, but is not limited to, about 2 to about 75 particles; about 10 to about 50 particles; about 15 to about 25 particles; or about 10 to about 5 In other embodiments, the unit dose of the immediate release dosage form of the present invention may include, but is not limited to, 0 particles. No particles, but about 50 to about 500 particles; about 75 to about 350 particles; about 100 to about 300 particles or may comprise about 150 to about 250 particles.

[0137] In various embodiments, the solid oral dosage form contains a therapeutically effective, antitussive, or analgesic effective amount of the active agent. The analgesic may include an analgesic (e.g., an opioid analgesic).

[0138] release rate The solid oral dosage forms disclosed herein can provide immediate release of the active agent. In embodiments, the solid oral dosage forms disclosed herein provide immediate release of an opioid analgesic. and is free of, or substantially free of, sustained release of an opioid analgesic.

[0139] In certain embodiments, the solid oral dosage forms disclosed herein have a pH of 0.1NH at about 37°C. In 900 ml of Cl, in USP Apparatus 1 (#40 mesh basket) At least about 80% of the opioid analgesic is dissolved within 15 minutes as measured by in vitro dissolution. %, at least about 85%, at least about 90%, at least about 95%, or at least It releases about 98%.

[0140] In certain embodiments, the solid oral dosage forms disclosed herein have a viscosity of 0.1 N HCl at 37° C. In a 900 ml container, in a USP Apparatus 1 (#40 mesh basket) At least approximately 80% of the opioid analgesic is dissolved within 30 minutes as measured by in vitro dissolution , at least about 85%, at least about 90%, at least about 95%, or at least about Releases 98%.

[0141] In certain embodiments, the solid oral dosage forms disclosed herein have a viscosity of 0.1 N HCl at 37° C. In a 900 ml container, in a USP Apparatus 1 (#40 mesh basket) At least approximately 80% of the opioid analgesic is dissolved within 45 minutes as measured by in vitro dissolution , at least about 85%, at least about 90%, at least about 95%, or at least about Releases 98%.

[0142] In certain embodiments, the solid oral dosage forms disclosed herein are prepared in 0.1 N HCl at room temperature. In 900 ml, in USP Apparatus 1 (#40 mesh basket) At least about 80% of the opioid analgesic is dissolved within 60 minutes as measured by in vitro dissolution; At least about 85%, at least about 90%, at least about 95%, or at least about 9 Releases 8%.

[0143] In some embodiments, the solid oral dosage forms disclosed herein comprise a gelling agent composition in delayed release form. wherein the gelling agent composition comprises a gelling agent and an enteric coating. The compositions can be processed by rotor powder layering, fluid bed granulation, roller compaction, fluid bed coating (Urs and combinations thereof. It can be manufactured.

[0144] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. The rotor layer and enteric coating contained about 10% (w / w) of enteric material based on the total weight of the pellet. The recovery of the opioid analgesic was determined by the percentage of solid pellets that remained intact. The oral dosage form is dissolved in about 5 ml to about 10 ml of tap water at room temperature without stirring, and the resulting solution needle penetration test by aspirating with an 18, 22, 25, or 27 gauge needle Based on this, it is less than about 15%.

[0145] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. The rotor layer and enteric coating contained about 10% (w / w) of enteric material based on the total weight of the pellet. The recovery of the opioid analgesic was determined by the percentage of solid pellets that remained intact. The oral dosage form is dissolved in about 5 ml to about 10 ml of tap water while stirring at room temperature, and the resulting solution is Needle penetration test by aspirating the liquid through an 18, 22, 25, or 27 gauge needle Based on this, it is approximately less than 5%.

[0146] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. The rotor layer and enteric coating contained about 30% (w / w) of enteric material based on the total weight of the pellet. The recovery of the opioid analgesic was determined by the percentage of solid pellets that remained intact. The oral dosage form is dissolved in approximately 10 ml of tap water at room temperature with or without stirring, and the resulting needle by withdrawing the solution into an 18, 22, 25, or 27 gauge needle. Based on passing tests, it is approximately less than 20%.

[0147] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. The rotor layer and enteric coating contained about 30% (w / w) of enteric material based on the total weight of the pellet. The recovery of the opioid analgesic was determined by the percentage of solid pellets that remained intact. The oral dosage form was dissolved in approximately 5 ml of tap water at room temperature without stirring, and the resulting solution was added to 18, 22 Based on needle penetration testing by aspirating with a 25-, 27-gauge needle, approximately 1 It is less than 0%.

[0148] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. The rotor layer and enteric coating contained about 30% (w / w) of enteric material based on the total weight of the pellet. The recovery of the opioid analgesic was determined by the percentage of solid pellets that remained intact. The oral dosage form was dissolved in approximately 5 ml of tap water with stirring at room temperature, and the resulting solution was diluted with 18,2 Based on needle penetration testing by aspirating with a 2, 25, or 27 gauge needle, approximately Less than 5%.

[0149] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. The recovery of the opioid analgesic contained in the top-sprayed granules remained intact. Dissolve the oral dosage form in approximately 5 to 10 ml of tap water at room temperature with or without stirring. and aspirate the resulting solution with an 18, 22, 25, or 27 gauge needle. Based on needle penetration tests, the figure is less than approximately 2%.

[0150] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. Includes roller-compacted and bottom-spray (enteric-coated) granules, Recovery of steroid analgesics was measured by stirring intact solid oral dosage forms at room temperature or after stirring. The resulting solution was dissolved in about 5 ml to about 10 ml of tap water without adding any other additives. or less than approximately 40% based on a needle penetration test using a 27-gauge needle , less than about 30%, less than about 10%, or less than about 8%.

[0151] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed release gelling agent composition, wherein the solid oral dosage form comprises a sustained release analgesic composition. The delayed release gelling agent composition is free or substantially free of an opioid analgesic drug composition. , rotor-granulated and enteric-coated pellets containing about 30% (w / w) of enteric material based on the total weight of the pellets. The recovery of the opioid analgesic is higher than that of the crushed solid pellets containing the coated pellets. The oral dosage form is dissolved in approximately 10 ml of tap water at room temperature with or without stirring, and the resulting needle by withdrawing the solution into an 18, 22, 25, or 27 gauge needle. Based on a pass-through test, it is less than about 15%, less than about 10%, or less than about 5%.

[0152] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain an immediate release opioid. and a delayed-release gelling agent particle, wherein the solid oral dosage form comprises a sustained-release The delayed release gelling agent composition is free or substantially free of an opioid analgesic composition, Includes roller-compacted and bottom-sprayed (enteric-coated) granules, and Recovery of opioid analgesics was determined by subjecting crushed solid oral dosage forms to stirring at room temperature or with stirring. Dissolve in approximately 10 ml of tap water without stirring, and measure the resulting solution at 18, 22, 25, or 2 Based on needle penetration tests using a 7-gauge needle, the rate was less than approximately 30%, approximately 25% %, or less than about 5%.

[0153] Active Agent The immediate release solid oral dosage forms according to the present disclosure contain various active agents and their pharmaceutically acceptable salts. Pharmaceutically acceptable salts include, but are not limited to, hydrochloride, hydrobromide, and the like. Inorganic acid salts such as sulfates and phosphates; formates, acetates, trifluoroacetates, maleates Salt, tartrate and other organic acid salts; methanesulfonate, benzenesulfonate, p-toluene Sulfonates such as benzosulfonates; alginates, aspartates, glutamates and metal salts such as sodium salts, potassium salts, and cesium salts; calcium alkaline earth metal salts such as ammonium salts and magnesium salts; triethylamine salts, pyridine salts, pico- Phosphorus salts, ethanolamine salts, triethanolamine salts, discyclohexylamine salts, Included are organic amine salts such as N,N'-dibenzylethylenediamine salts.

[0154] According to certain embodiments, any of the following active agents may be administered in an immediate release formulation disclosed herein: Can be used in solid oral dosage forms: ACE inhibitors, adenosine triphosphate (ATP), benzodiazepines, and benzodiazepines. Adrenergic neuron blocking agents, corticosteroids, corticosteroid biosynthesis inhibitors, alpha adrenergic agonists, alpha adrenergic antagonists, Selective alpha-2 adrenergic agonist, analgesic, antipyretic, anti-inflammatory, androgen , local and general anesthetics, anti-intoxicants, anti-androgens, anti-arrhythmics, anticholinergics, anticholinergics Esterase drugs, anticoagulants, antidiuretics, antiemetics, prokinetic drugs, antiestrogens, antifungals , antimicrobials, antimigraine drugs, antimuscarinics, antitumor drugs, antiparasitic drugs, antiparkinsonian drugs , antiplatelet agents, antiprogestins, antischizophrenic agents, antithyroid agents, antiviral agents, atypical Antidepressants, azaspirodecanediones, barbiturates, benzodiazepines, benzothiazides Azide, beta-adrenergic agonist, beta-adrenergic antagonist, selection Selective beta-1-adrenergic antagonist, selective beta-2-adrenergic agonist substances affecting the volume and composition of body fluids, butyrophenones, substances affecting calcification agents, calcium channel blockers, cardiovascular agents, catecholamines and sympathomimetics Stimulants, cholinergics, cholinesterase reactivators, contraceptives, dermatological agents, diphenylbromide Chilpiperidine, ergot alkaloids, estrogen, ganglionic blockers, ganglionic stimulants, folds Antihistamines, agents for controlling gastric acidity and treating peptic ulcers, antianemic agents, hormones , a 5-hydroxytryptamine antagonist, for treating hyperlipoproteinemia Drugs, hypnotics, immunosuppressants, methylxanthines, monoamine oxidase inhibitors, neuromuscular Blockers, organic nitrates, opioid agonists, opioid antagonists, pancreatic enzymes , phenothiazines, progestins, prostaglandins, drugs for treating psychiatric disorders , retinoids, sodium channel blockers, agents for spasticity and acute muscle spasms, Succinimide, testosterone, thioxanthine, hemolytic drugs, thyroid drugs, tricyclic antidepressants Drugs, inhibitors of tubular transport of organic compounds, uterine motility Drugs that affect the immune system, as well as mixtures thereof.

[0155] In certain embodiments, the active agent for the immediate release solid oral dosage forms disclosed herein is In certain embodiments, the active agent is an opioid Agonists, tranquilizers, CNS depressants, CNS stimulants, sedative-hypnotics, and mixtures thereof The compound may be selected from the group consisting of:

[0156] According to certain embodiments, the active agent may include an opioid analgesic. Useful opioid analgesics for the disclosed immediate release solid oral dosage forms include, but are not limited to: However, alfentanil, allylprozine, alphaprozine, anileridine, benzilmo Lupine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine , desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihy Drocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthio Ambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptadine, ethi methylthiambutene, ethylmorphine, etonitazene, etorphine, dihydroethoxybenzone Fentanyl, fentanyl and derivatives, hydrocodone, hydromorphone, hydroxypethidine , isomethadone, ketobemidone, levorphanol, levophenacylmorphan, Rofe methanil, meperidine, meptazinol, methazodine, methadone, metopon, morphine, Myrofin, Narceine, Nicomorphine, Norlevorphanol, Normethadone, Nalor fin, nalbufen, normorphine, norpipanone, opium, oxycodone, oximo Luhon, Papaveretam, Pentazocine, Phenadoxone, Phenomorphan, Phenazoxine phenopiperazine, piminodine, piritramide, propeptadine, promedol, Properidine, propoxyphene, sufentanil, tilidine, tramadol, and Pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof, and mixtures of any of the foregoing This includes things etc.

[0157] In certain embodiments, the opioid for the immediate release solid oral dosage form disclosed herein Painkillers include morphine, hydromorphone, hydrocodone, oxycodone, codeine, and levofloxacin. dihydrocodeine, dihydromorphine, oxymorphone, phenanol, meperidine, dihydrocodeine, dihydromorphine, lantanil, buprenorphine, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof The compound may be selected from the group consisting of: hydroxybenzoates, ...

[0158] Examples of other possible active agents include, but are not limited to, antihistamines (e.g., dimensolone, Hydrinate, diphenhydramine, chlorpheniramine and dexchlor maleate nonsteroidal anti-inflammatory drugs (e.g., aspirin, celecoxib, Cox- 2 inhibitors, ibuprofen, indomethacin, diclofenac, naproxen, benox profen, flurbiprofen, fenoprofen, flubufen, ketoprofen, Indoprofen, pyroprofen, carprofen, oxaprozin, pramoprofen phenytoin, muroprofen, trioxaprofen, suprofen, aminoprofen, thiaprophen Lofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin , zomepirac, tiopinac, zidometacin, acemetacin, fentiazac, clidanac , oxypinac, mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid, Rufenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam cam, its pharmaceutically acceptable salts and mixtures thereof), and acetaminophen, antiemetics ( metoclopramide, methylnaltrexone), antiepileptic drugs (e.g., phenylalanine, azepam, meprobumate, and nitrazepam), vasodilators (e.g., nifedipine, papaverine, diltiazem and nicardipine), antitussives and expectorants (e.g., antiasthmatics (e.g., theophylline), antacids, antispasmodics (e.g., atropine, scopolamine), antidiabetic drugs (e.g., insulin), diuretics (e.g., , ethacrynic acid, bendrofluthiazide), antihypotensive drugs (e.g., propranolol, lonidine), antihypertensives (e.g., clonidine, methyldopa), bronchodilators (e.g., albuterol), steroids (e.g., hydrocortisone, triamcinolone, prednisolone, antihemorrhoids (antihemorrhoidal drugs), antibiotics (e.g., tetracycline), oidals), hypnotics, psychotropic drugs, antidiarrheals, mucolytics, sedatives, decongestants (e.g. (e.g., pseudoephedrine), laxatives, vitamins, stimulants (phenylpropanolamine and cannabinoids, as well as pharmaceutically acceptable salts thereof; Hydrates, solvates, and prodrugs are included.

[0159] The active agent may also be a benzodiazepine, a barbiturate, a stimulant, or a mixture thereof. The term "benzodiazepine" includes benzodiazepines and drugs that depress the central nervous system. This refers to drugs that are derivatives of benzodiazepines that can be obtained by benzodiazepine therapy. Benzodiazepines include, but are not limited to: However, alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam Azepam, estazolam, flurazepam, halazepam, ketazolam, lorazepam, nitrazepam Zepam, oxazepam, prazepam, quazepam, temazepam, triazolam, methylphenidate phenidate, as well as its pharmaceutically acceptable salts, hydrates, solvates, prodrugs and Benzodiazepine antagonists that can be used as active agents include benzodiazepines and mixtures thereof. Examples of antihistamines include, but are not limited to, flumazenil, as well as pharmaceutically acceptable salts thereof. , hydrates, solvates and mixtures thereof.

[0160] The term "barbiturate" refers to barbituric acid (2,4,6-trioxohexahydroxybenzoates). Barbiturates are sedative-hypnotic drugs derived from benzodiazepines (benzopyrimidines). Although not used, amobarbital, aprobarbital, butabarbital, butalbital methohexital, mephobarbital, metharbital, pentobarbital, phen Novarbital, secobarbital, and their pharmaceutically acceptable salts, hydrates, and solvates. This includes solvates, prodrugs, and mixtures. Rubiturate antagonists include, but are not limited to, amphetamines, as well as Pharmaceutically acceptable salts, hydrates, solvates and mixtures thereof are included.

[0161] The term "stimulant" includes, but is not limited to, dextroamphetamine resin complexes. Compounds such as dextroamphetamine, methamphetamine, and methylphenidate and pharmaceutically acceptable salts, hydrates, and solvates thereof, as well as Stimulant antagonists that can be used as active agents include: These include, but are not limited to, benzodiazepines, as well as their pharmaceutically acceptable salts, hydrates, Solvates and mixtures are included.

[0162] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain 100 mg of active ingredient per dosage form. Medications (e.g., opioid analgesics) approximately 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, Approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3 %, about 4%, about 5%, about 6%, or about 7% to about 8%, about 9%, about 10%, about 11%, about 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, approximately 45%, approximately 50%, approximately 60%, approximately In certain embodiments, the present invention may comprise about 70%, or about 80% (w / w). The instant release solid oral dosage forms shown contain approximately 0.5 mg of active agent (e.g., opioid analgesic) per dosage form. It may contain 1% to about 80%, about 0.5% to about 30%, or about 1% to about 10% (w / w) .

[0163] Delayed-Release Gelling Agent Composition In certain embodiments, the delayed release gelling agent compositions disclosed herein comprise a gelling agent and In certain embodiments, the delayed release gelling agent composition may comprise one or more enteric materials. Each delayed-release gelling agent particle may be in the form of a plurality of particles, each of which is (i) coated with an enteric material; (ii) coated with a gelling agent and overcoated with an enteric material; coated inert cores (e.g., beads); or (iii) enteric matrices. The substance may include a gelling agent dispersed therein. In certain embodiments, the delayed release gelling agent composition In addition to the agent, the dosage form may contain an immediate release form of a gelling agent in an amount that does not interfere with the immediate release characteristics of the dosage form. It may include.

[0164] In certain embodiments, the gelling agent used in the immediate release solid oral dosage forms disclosed herein Agents include, but are not limited to, starch and starch derivatives, cellulose derivatives (e.g. , Sodium carboxymethylcellulose, Methylcellulose, Hydroxyethylcellulose cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose), Pulgite, bentonite, dextrin, alginate, carrageenan, gums (e.g., Gum tragacanth, gum arabic, guar gum, and xanthan gum), pectin, gelatin Acrylic crosslinked with allyl ethers of polyalcohols such as tin, kaolin, and carbomer High molecular weight polymers of acrylic acid (also called cross-linked polyacrylic acid), polyvinylpyrrolidone, poly Polyethylene oxide, polyvinyl alcohol, curdlan, furcellaran, egg white powder, Lactalbumin, soy protein, chitosan, surfactant, mixed surfactant / wetting agent The emulsion may include those selected from emulsion systems, emulsifiers, other polymeric materials, and mixtures thereof.

[0165] In certain embodiments, the gelling agent is polyethylene oxide, xanthan gum, carbohydrate The polymer may be selected from the group consisting of saccharides, polysaccharides, and mixtures thereof.

[0166] In certain embodiments, the gelling agent is a polymer such as a polysaccharide (e.g., a gelling polymer ), specifically microbial polysaccharides such as xanthan gum. The gelling agent is a neutral pH gel such as polyacrylic acid, specifically carbomer homopolymer. In certain embodiments, the gelling agent may be an anionic polymer in aqueous solution. Xanthan gum and carbomer homopolymers may also be used.

[0167] The gelling agent was mixed with about 0.5 ml to about 10 ml of tap water at room temperature (crushed or The viscosity of the dosage form (which remains intact) is such that it can be drawn into a syringe or administered parenterally or nasally. The ability of an active agent (e.g., an opioid analgesic) to be absorbed systemically when administered by the The active ingredient may be included in the immediate release solid oral dosage form in an amount to prevent or reduce the effectiveness of the active ingredient. In certain embodiments, the viscosity of the tampered dosage form is determined by the viscosity of the dosage form when administered parenterally or intravenously. may be inappropriate for

[0168] In some embodiments, the intact solid oral dosage form is dissolved in about 0.5 ml to about 10 ml of water at room temperature. The viscosity of the solution obtained after 5 minutes in 1 (measured, for example, by a rotational viscometer) is about 10 cP or more. , about 25 cP or more, about 50 cP or more, about 75 cP or more, about 100 cP or more, about 125 cP More than ~ about 150cP or more, about 175cP or more, about 200cP or more, about 300cP or more, about 400cP or more, about 500cP or more, about 750cP or more, about 1000cP or more, about 200 0cP or more, about 3000cP or more, about 4000cP or more, about 5000cP or more, about 750 0cP or more, approximately 10,000cP or more, approximately 15,000cP or more, approximately 20,000cP or more Above, about 25,000cP or more, about 50,000cP or more, about 75,000cP or more, about 1 00,000cP or more, approximately 125,000cP or more, or approximately 150,000cP or more be.

[0169] In some embodiments, the intact solid oral dosage form is dissolved in about 0.5 ml to about 10 ml of water at room temperature. The viscosity of the solution obtained after 5 minutes in 1 L (measured, for example, from a rotational viscometer) is about 10-150 ,000cP, approx. 25~10,000cP, approx. 25~1000cP, approx. 50~1000c P, approx. 75~1000cP, approx. 25~500cP, approx. 50~500cP, approx. 75~500 cP, about 25-200 cP, about 50-200 cP, or about 75-200 cP. It is possible.

[0170] In some embodiments, the tampered solid oral dosage form is dispensed into about 0.5 ml to about 10 ml of water at room temperature. The viscosity of the solution obtained in 10 ml at the second minute is about 10 cP or more, about 25 cP or more, and about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more and about 150 cP or more Above, about 175cP or more, about 200cP or more, about 300cP or more, about 400cP or more, about 5 00cP or more, about 750cP or more, about 1000cP or more, about 2000cP or more, about 300 0cP or more, about 4000cP or more, about 5000cP or more, about 7500cP or more, about 10, 000cP or more, about 15,000cP or more, about 20,000cP or more, about 25,000c P or more, about 50,000cP or more, about 75,000cP or more, about 100,000cP or more , about 125,000 cP or more, or about 150,000 cP or more. In this example, the tampered solid oral dosage form is placed in about 0.5 ml to about 10 ml of water at room temperature for 2 minutes. The viscosity of the solution obtained is about 10 to 150,000 cP, about 25 to 10,000 cP, Approx. 25~1000cP, Approx. 50~1000cP, Approx. 75~1000cP, Approx. 25~500 cP, approx. 50~500cP, approx. 75~500cP, approx. 25~200cP, approx. 50~200 cP, or may be in the range of about 75-200 cP.

[0171] In some embodiments, the intact solid oral dosage form is dissolved in about 0.5 mL of 0.1 N HCl at room temperature. The viscosity of the solution obtained in 5 minutes from about 10 ml to about 50 cP is less than about 40 cP. , less than about 30 cP, less than about 20 cP, less than about 10 cP, less than about 5 cP, or less than about 2 cP It is full.

[0172] In some embodiments, the tampered solid oral dosage form is diluted with about 0.1 N HCl at room temperature. The viscosity of the solution obtained in 0.5 ml to about 10 ml at 5 minutes is less than 50 cP, about 40 cP less than about 30 cP, less than about 20 cP, less than about 10 cP, less than about 5 cP, or less than about 2 cP It is less than P.

[0173] In some embodiments, the intact solid oral dosage form is dissolved in about 0.5 mL of 0.1 N HCl at room temperature. The viscosity of the solution obtained at 5 minutes in a volume of about 10 ml to about 10 ml is Viscosity of the solution obtained at 5 minutes in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature within about 30%, about 20%, about 10%, or about 5% of the

[0174] In certain embodiments, the weight of the gelling agent contained in the immediate release dosage form of the present invention is In another embodiment, the weight of the active ingredient (e.g., an opioid analgesic) is less than or equal to the weight of the active ingredient (e.g., an opioid analgesic). The weight of the gelling agent contained in the time-release dosage form is less than the weight of the active agent. In this embodiment, the weight of the gelling agent contained in the immediate release dosage form of the present invention exceeds the weight of the active agent. Rotate.

[0175] In certain embodiments, the immediate release dosage forms of the present invention comprise a ratio of about 1:40 to about 40:1; 35~35:l; 1:30~30:l; 1:25~25:l; 1:20~approx. 20:l; approx. 1:15~approx. 15:l; approx. 1:10~approx. 10:l; approx. 1:8~approx. 8:1; approx. 1:5 to approx. 5:1; approx. 1:3 to approx. 3:1; approx. 1:1.5 to approx. 1.5:1; approx. 1:1.25 ~approx. 1.25:1; 1:1 to approx. 40:1; approx. 1:1 to approx. 35:1; approx. 1:1 to approx. 30:1 ;About 1:1 to about 25:1;About 1:1 to about 20:1;About 1:1 to about 15:1;About 1:1 to about 10:1; about 1:1 to about 8:1; about 1:1 to about 5:1; about 1:1 to about 3:1; about 1:1 Approximately 1.5:1; Approximately 1:1 to 1.25:1; 1:40 to 1:1; Approximately 1:35 to 1:1 ;Approx. 1:30 to 1:1;Approx. 1:25 to 1:1;Approx. 1:20 to 1:1;Approx. 1:15 Approximately 1:1; Approximately 1:10 to approximately 1:1; Approximately 1:8 to approximately 1:1; Approximately 1:5 to approximately 1:1; Approximately 1:3 to about 1:1; about 1:1.5 to about 1:1; or about 1:1.25 to about 1:1 of the active agent (e.g. The weight ratio of the active ingredient (e.g., an opioid analgesic) to the gelling agent is also included.

[0176] In certain embodiments, the immediate release solid oral dosage forms disclosed herein contain Gelling agent: about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6 %, approximately 0.7%, approximately 0.8%, approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, Approximately 6%, or approximately 7% to approximately 8%, approximately 9%, approximately 10%, approximately 11%, approximately 12%, approximately 13%, approximately 14%, approximately 15%, approximately 16%, approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 25%, approximately 30%, about 35%, about 40%, about 45%, about 50%, about 55%, or about 60% (w / w In certain embodiments, the dosage form may comprise about 0.5 wt. of gelling agent based on the total weight of the dosage form. It may contain 1% to about 60%, about 0.5% to about 20%, or about 1% to about 10% (w / w). do.

[0177] According to some embodiments, the delayed release gelling agent composition is a rotor layered and enteric coated coated pellets, top sprayed granules, roller compacted pellets, bottom sprayed coated granules (e.g., Wurster-coated granules), or combinations thereof The compound may contain one or more of the following:

[0178] In certain embodiments, when the delayed release gelling agent composition comprises top spray granules, About 90% to about 100%, about 9% of the top spray granules incorporated into the immediate release solid oral dosage form 5% to approximately 100%, or approximately 99% to approximately 100% is a 100 mesh screen, 200 mesh In certain embodiments, the granules may be held in one or more of a mesh screen, a mesh screen, and a mesh pan. When the delayed release gelling agent composition comprises top spray granules, the immediate release solid oral dosage form About 20% to about 50%, about 30% to about 45%, or about 40% may be retained in the 100 mesh screen. In certain embodiments, delayed release When the gelling agent composition comprises top spray granules, it can be incorporated into an immediate release solid oral dosage form. About 20% to about 50%, about 30% to about 45%, or about 40% of the top spray granules are 2 In certain embodiments, the delayed release gelling agent may be retained in a 00 mesh screen. When the composition comprises top spray granules, the tops incorporated into the immediate release solid oral dosage form About 10% to about 30%, about 15% to about 25%, or about 20% of the play granules are 200 mesh. It can pass through the screen.

[0179] In certain embodiments, when the delayed-release gelling agent composition comprises roller-compacted pellets, The pellets have a bulk density ranging from about 0.4 g / ml to about 0.6 g / ml, or about 0.5 The tap density may range from 5 g / ml to about 0.65 g / ml. In this case, the term "tapped density" refers to the density measured by mechanically tapping a container containing a powder sample. This refers to the increased bulk density achieved after heating.

[0180] enteric-coated substances In certain embodiments, the enteric material is a gel in one or more delayed-release gelling agent particles. In other embodiments, the enteric material may be overcoated with a suspending agent(s). is a matrix material (unit or multiparticulate) in which the delayed-release gelling agent composition may be dispersed. ) may be part of

[0181] In certain embodiments, the enteric material is (i) soluble at a pH greater than about 5.5; (ii) (iii) insoluble at a pH below about 5.5; or (iv) insoluble at a pH above 5.5. However, it is insoluble at pH below 5.5.

[0182] In certain embodiments, the enteric material used to coat the gelling agent is Composed of cellulose-based materials, acrylic acid polymers, methacrylic acid polymers and mixtures thereof It may be selected from the group:

[0183] According to certain embodiments, the enteric material is methacrylic acid / methyl methacrylate, ... Acrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate / methacrylic acid Acid Methyl Copolymer, Shellac, Hydroxypropyl Methylcellulose Phthalate, Hydroxylpropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose Cellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate In certain embodiments, the enteric material may be selected from the group consisting of: , methacrylic acid / ethyl acrylate copolymer.

[0184] According to certain embodiments, the dosage form contains about 0.1%, about 0.5%, or about 1% of enteric material by weight of the dosage form. 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7%, approximately 0.8%, Approximately 0.9%, approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9 %, or about 10% to about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, Approximately 17%, approximately 18%, approximately 19%, approximately 20%, approximately 25%, approximately 30%, approximately 35%, approximately 40%, In certain embodiments, the dosage form may comprise about 45%, or about 50% (w / w). About 0.1% to about 50%, about 1% to about 20%, or about 2% to about 1% of the enteric material based on the total weight of the formulation It may contain about 15% (w / w).

[0185] Certain solid oral dosage forms include a delayed-release gelling agent composition in the form of one or more particles. According to this embodiment, each delayed-release gelling agent particle contains, by weight of each delayed-release gelling agent particle, Enteric coating material: about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9% , about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% to about 20%, about 21%, approximately 22%, approximately 23%, approximately 24%, approximately 25%, approximately 26%, approximately 27%, approximately 28%, approximately 29%, approximately 30%, approximately 31%, approximately 32%, approximately 33%, approximately 34%, approximately 35%, approximately 40%, It may comprise about 50%, about 60%, about 70%, or about 80% (w / w). In the form, the dosage form contains about 10% to about 30% enteric material by weight of each delayed-release gelling agent particle. , or about 12% to about 25% (w / w).

[0186] In certain embodiments, the delayed-release gelling agent composition is a rotor layer and an enteric coated The pellets comprise enteric-coated pellets, the pellets comprising an amount of the delayed-release gelling agent composition that is greater than or equal to the total weight of the delayed-release gelling agent composition. About 5% to about 35% of substance, about 5% to about 15%, about 15% to about 25%, about 25% to about 35%, It comprises about 10%, or about 30% (w / w).

[0187] According to certain embodiments, the immediate release solid oral dosage forms disclosed herein have a molecular weight of about 1:40 ~approx. 40:1, approx. 1:30~approx. 30:1, approx. 1:20~approx. 20:1, approx. 1:15~approx. 15 :1, about 1:10 to about 10:1, about 1:8 to about 8:1, about 1:5 to about 5:1, about 1:3 Approximately 3:1, approximately 1:1.5 to approximately 1.5:1, approximately 1:1 to approximately 40:1, approximately 1:1 to approximately 30:1 , about 1:1 to about 20:1, about 1:1 to about 15:1, about 1:1 to about 8:1, about 1:1 to about 5 :1, about 1:1 to about 3:1, about 1:1 to about 1.5:1, about 1:40 to about 1:1, about 1:3 0 to approximately 1:1, approximately 1:20 to approximately 1:1, approximately 1:15 to approximately 1:1, approximately 1:8 to approximately 1:1, approximately A ratio of gelling agent to intestinal fluid of 1:5 to about 1:1, about 1:3 to about 1:1, or about 1:1.5 to about 1:1 The weight ratio of the solvent to the solvent may be:

[0188] aversive agents The immediate release solid oral dosage forms according to the present disclosure further prevent unauthorized use of the active agent contained therein. The substance may contain one or more aversive agents to deter the development of a toxic substance. Such aversive agents include emetics, antihistamines, and the like. The aversive agent may be selected from the group consisting of an antagonist, a bittering agent, an irritant, and mixtures thereof. a matrix comprising an active agent (e.g., an opioid analgesic) and a delayed-release gelling agent composition. Incorporated into tablets, or into particles added separately within capsules, or as an additional tableting excipient It can be incorporated.

[0189] Exemplary emetics include, but are not limited to, methylcephalin, cephalin, ethoxylated methyl ... Methine, psychotrin, O-methylpsychotrin, emethamine, ipecamine, hydroipe These include citric acid, thiamin, tetronic acid and mixtures thereof.

[0190] Exemplary antagonists include, but are not limited to, naltrexone, naloxone, Nalmefene, cyclazacine, levallorphan, their pharmaceutically acceptable salts, and solvates thereof This includes the compounds, their prodrugs, and mixtures thereof.

[0191] Exemplary bittering agents include, but are not limited to, flavor oils, flavoring fragrances, oleoresins, plant extracts, and the like. Extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, In certain embodiments, the anti-inflammatory agents include quinine sulfate, denatonium benzoate, and mixtures thereof. The bittering agents are spearmint oil, peppermint oil, eucalyptus oil, nutmeg oil, and AllSpa. The oil may be selected from the group consisting of sucralose, mace, bitter almond oil, menthol and mixtures thereof. In certain embodiments, the fruit extracts include lemon, orange, lime, and grapefruit. It may be derived from fruits containing citric acid, ...

[0192] Exemplary irritants include, but are not limited to, surfactants, capsaicin or capsaicin. Capsaicin analogs include resiniferatoxin and its mixtures. , tiniatoxin, heptanoyl isobutyramide, heptanoyl guaiacylamide, Sobutyramide, Guaiacylamide, Dihydrocapsaicin, Homovanillyl Octyl Ester The carboxylic acid may be selected from the group consisting of ether, nonanoyl vanillyl amide, and mixtures thereof.

[0193] Exemplary surfactants include, but are not limited to, poloxamer, sorbitan monoester Contains glyceryl monooleate, sodium lauryl sulfate, or a combination thereof In certain embodiments, the surfactant may be sodium lauryl sulfate. .

[0194] In certain embodiments, the stimulant is present in the dosage form, e.g., in an amount of about 1000 mg of stimulant by weight of the dosage form. 0.1%, approximately 0.2%, approximately 0.3%, approximately 0.4%, approximately 0.5%, approximately 0.6%, approximately 0.7% ,approximately 0.8%,approximately 0.9%,approximately 1%,approximately 2%,approximately 3%,approximately 4%,approximately 5%,approximately 6%,approximately 7% , about 8%, about 9%, or about 10% to about 11%, about 12%, about 13%, about 14%, about 15 %, approx. 16%, approx. 17%, approx. 18%, approx. 19%, approx. 20%, approx. 25%, approx. 30%, approx. 35 %, about 40%, about 45%, or about 50% (w / w). In the dosage form, the stimulant may be present in an amount of about 0.1% to about 30%, about 0.5% to about 10%, or about 10% to about 20%, based on the total weight of the dosage form. It may contain 20%, or about 1% to about 10% (w / w).

[0195] additives The immediate release solid oral dosage forms according to the present disclosure comprise one or more pharmaceutically acceptable carriers and Examples of possible pharmaceutically acceptable carriers and additives are provided herein by reference. Handbook of Pharmaceutical Exci pients, American Pharmaceutical Associat ion (6th Edition, 2009 Publication) Suitable carriers and additives include, but are not limited to, plasticizers, colorants, lubricants, , bulking agents, thermal lubricants, antioxidants, buffers, disintegrants, binders, diluents, fluidization promoters, anti-adhesives Adhesives, sweeteners, chelating agents, flavoring agents, surfactants, solubilizers, stabilizers, hydrophilic polymers -, hydrophobic polymers, waxes, lipophilic substances, absorption enhancers, preservatives, absorbents, cross-linking agents, biocompatible The adhesive may include a viscous polymer, a pore former, an osmolality adjusting agent, a polycarboxylic acid, or a combination thereof. can be.

[0196] According to certain embodiments, the dosage form may include a plasticizer. Additionally, the plasticizer interacts with the hydrophobic material, resulting in a lower viscosity compared to the mixture without the plasticizer. Suitable plasticizers include, but are not limited to, low molecular weight polyisocyanates. Polymers, oligomers, copolymers, oils, small organic molecules, small molecules with aliphatic hydroxyl groups Polyol, ester type plasticizer, glycol ether, poly(propylene glycol) , multiblock polymers, single block polymers, low molecular weight poly(ethylene glycol) ethanol), citrate ester type plasticizer, triacetin, propylene glycol and glycerin Such plasticizers include ethylene glycol, 1,2-butylene glycol, 2,3-butylene glycol, styrene glycol, diethylene glycol, triethylene glycol Ethylene glycol, tetraethylene glycol and other poly(ethylene glycol) compounds Monopropylene glycol monoisopropyl ether, propylene glycol monoisopropyl ether ethyl ether, ethylene glycol monoethyl ether, diethylene glycol monoethyl ether Ether, Sorbitol Lactate, Ethyl Lactate, Butyl Lactate, Ethyl Glycolate, Sebaceous Dibutyl phosphate, acetyl tributyl citrate, triethyl citrate, glycerin monostearate Lycerin, Polysorbate 80, Acetyltriethyl Citrate, Tributyl Citrate and Allyl glycolate and mixtures thereof may also be included. In certain embodiments, the plasticizer , about 5% or less, or about 4% or less, or about 2% or less, or 0% (i.e., non-plasticizer An exemplary plasticizer is available from Evonik Industries. Glyceryl monostearate, such as PlasaACRYL® HTP20, is available. The plasticizer may be a polyethylene-based plasticizer.

[0197] According to certain embodiments, the dosage form may include a glidant. It is an additive that improves the flow properties of compressible powders such as pharmaceutical ingredients or granules. In an embodiment, the glidant is silicon dioxide. Two exemplary glidants are colloidal silica and silica. Silicon dioxide (CAB-O-SIL®) and Quso (Phila Q) The amount of fluidization promoter that can be used is about 0.1 The range is from about 5% by weight to about 5% by weight.

[0198] Suitable diluents useful in dosage forms according to the present disclosure include, but are not limited to, lactose Lactose USP, Lactose USP (Anhydrous), Lactose USP (Spray-Dried), Starch USP , directly compressible starch, mannitol USP, sorbitol, dextrose monohydrate Microcrystalline Cellulose NF, Dicalcium Phosphate Dihydrate NF, Sucrose-based Diluent, refined sugar, monocalcium sulfate monohydrate, calcium sulfate dihydrate NF, calcium lactate sodium trihydrate granules NF, dextrates NF (e.g., Emdex™), dextrose trose (e.g., Cerelose™), inositol, Maltrons (trademarks) Hydrolyzed grain solids, amylose, powdered cellulose, such as Mor-Rex™ and Mor-Rex™ (e.g., Elcema™), calcium carbonate, glycine, bentonite, poly In certain embodiments, the dosage forms described herein include: About 0.1% to about 99%, or about 10% to about 80%, or about 15% to about It may contain in the range of 70% diluent.

[0199] Suitable lubricants include, but are not limited to, glyceryl behenate (Compritol (trademark 888), metal stearates (e.g., magnesium stearate, calcium stearate), and sodium), stearic acid, hydrogenated vegetable oil (e.g., Sterotex™ ), talc, waxes such as beeswax and carnauba wax, silica, fume silica, colloidal silica Calcium stearate, long chain fatty alcohol, boric acid, sodium benzoate and and sodium acetate, sodium chloride, DL-leucine, polyethylene glycol (e.g. , Carbowax™ 4000 and Carbowax™ 6000), Olay Sodium phosphate, sodium benzoate, sodium acetate, sodium lauryl sulfate, stearyl alcohol Sodium allyl fumarate (Pruv™), magnesium lauryl sulfate, stearyl Acid, Stearyl Alcohol, Mineral Oil, Paraffin, Microcrystalline Cellulose, Glycerin, Propanol In certain embodiments, the dosage form comprises: One or more lubricants are present in an amount of about 0.1% to about 15%, or about 0.25% to about 15% of the total weight of the dosage form. Magnesium stearate may be present in an amount of about 10%, or about 1% to about 8% of the dosage form. It is a preferred lubricant for use in certain embodiments.

[0200] Suitable anti-adherents include, but are not limited to, talc, corn starch, colloids, Silicon dioxide (Cab-O-Sil™), DL-leucine, sodium lauryl sulfate In certain embodiments, the dosage form contains an anti-adherent agent about 0.1% to about 15%, or about 0.25% to about 10%, or about 1% of the total weight of the dosage form It may be present in an amount of up to about 8%.

[0201] Other additives (such as colorants, flavors, and sweeteners) should be used without regard to their detrimental effect on the stability of the dosage form. It can be used in dosage form embodiments where little or no do.

[0202] Abuse prevention extraction In certain embodiments of the immediate release solid oral dosage forms described herein, the active agent from the dosage form Recovery of the drug was determined by immersing the intact solid oral dosage form in 5 ml of solvent (e.g., tap water) at room temperature with stirring. Dissolve in 1 ml of water and aspirate the resulting solution with an 18, 22, 25, or 27 gauge needle. Based on needle penetration tests, the results were less than approximately 40%, less than approximately 30%, less than approximately 20%, It may be less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%. In certain embodiments, dissolution occurs in about 1 to about 60 minutes, e.g., about 5 minutes, about 10 minutes, about 15 minutes, or the like. , for a period of about 30 minutes or about 45 minutes.

[0203] In certain embodiments, the recovery of the active agent from the dosage form is determined based on the percentage of the intact solid oral dosage form. Dissolve in 10 ml of a solvent (tap water, etc.) while stirring at room temperature, and add 18 ml of the resulting solution. Based on needle penetration testing by aspirating with a 22, 25, or 27 gauge needle , less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6% , less than about 4%, or less than about 2%.

[0204] In certain embodiments, the recovery of the active agent from the dosage form is determined based on the percentage of the intact solid oral dosage form. Dissolve in 5 ml of a solvent (such as tap water) at room temperature without stirring, and add 18,2 Based on needle penetration testing by aspirating with a 2, 25, or 27 gauge needle, approximately Less than 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, about It may be less than 4%, or less than about 2%.

[0205] In certain embodiments, the recovery of the active agent from the dosage form is determined based on the percentage of the intact solid oral dosage form. Dissolve in 10 ml of a solvent (such as tap water) at room temperature without stirring, and add 18 ml of the resulting solution. Based on needle penetration testing by aspiration with a 22-, 25-, or 27-gauge needle, Less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, It may be less than about 4%, or less than about 2%.

[0206] In certain embodiments, the recovery of the active agent from the dosage form is determined by crushing the solid oral dosage form. Dissolve in 10 ml of a solvent (such as tap water) while stirring at room temperature, and add the resulting solution to 18. Based on needle penetration testing by aspiration with a 22-, 25-, or 27-gauge needle, Less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, It may be less than about 4%, or less than about 2%.

[0207] In certain embodiments, the recovery of the active agent from the dosage form is determined by crushing the solid oral dosage form. Dissolve in 5 ml of a solvent (such as tap water) while stirring at room temperature, and add the resulting solution to 18,2 Based on needle penetration testing by aspirating with a 2, 25, or 27 gauge needle, approximately Less than 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, about It may be less than 4%, or less than about 2%.

[0208] In certain embodiments, the recovery of the active agent from the dosage form is determined by crushing the solid oral dosage form. Dissolve in 10 ml of a solvent (such as tap water) at room temperature without stirring, and add the resulting solution to 18,2 Based on needle penetration testing by aspirating with a 2, 25, or 27 gauge needle, approximately Less than 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, about It may be less than 4%, or less than about 2%.

[0209] In certain embodiments, the recovery of the active agent from the dosage form is determined by crushing the solid oral dosage form. Dissolve in 5 ml of a solvent (such as tap water) at room temperature without stirring, and then add the resulting solution to 18, 22 Based on needle penetration testing by aspirating with a 25-, 25-, or 27-gauge needle, approximately 4 Less than 0%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4 %, or may be less than about 2%.

[0210] In certain embodiments, the intact solid oral dosage form is dissolved in about 5 ml of water at room temperature for 5 minutes. The viscosity of the solution obtained at room temperature and the viscosity of the solution obtained at room temperature from the intact solid oral dosage form were measured. The viscosity ratio of the solution obtained at 5 minutes in 100 ml to that of the solution obtained at 5 minutes in 100 ml is about 10:1 or more, about 15:1 or more, about 20:1 or more :1 or greater, about 25:1 or greater, or about 30:1 or greater.

[0211] Collapse In certain embodiments, the intact immediate release solid oral dosage forms disclosed herein are About 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or 1 minute to about 2 minutes, 3 minutes, 4 minutes, 5, 6, 7, 8, 9, 10, 15, 20, 25, or up to 30 minutes In certain embodiments, the intact instantaneous disintegration time disclosed herein is in the range of The release solid oral dosage form may be dissolved in water for about 10 seconds to about 30 minutes, about 1 minute to about 10 minutes, or has a disintegration time ranging from about 10 seconds to about 2 minutes.

[0212] In certain embodiments, the intact immediate release solid oral dosage forms disclosed herein are In SGF, for about 10 seconds, 20 seconds, 30 seconds, 40 seconds, 50 seconds, or 1 minute to about 2 minutes. minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, In certain embodiments, the compositions disclosed herein have disintegration times ranging from 10 minutes to 30 minutes. Intact immediate release solid oral dosage forms may be prepared in SGF from about 10 seconds to about 30 minutes, from about 1 minute to about 1 minute. The disintegration time ranges from about 10 seconds to about 10 minutes, or from about 10 seconds to about 2 minutes.

[0213] method Treatment method Conditions or pathologies that may be treated by the dosage forms described herein include, but are not limited to: is inhibited, reduced, or alleviated by opioid receptor activation This may include symptoms or symptoms of one or more of the following: nervous system, vascular system, gastrointestinal system, pulmonary system, and heart. refers to a condition or symptom associated with multiple conditions. Examples of such conditions are pain, pulmonary edema, cough and and diarrhea.

[0214] According to various embodiments of the present disclosure, dosage forms as described herein, e.g., immediate release Treating pain by administering a solid oral dosage form to a patient in need thereof; and In embodiments, the dosage forms described herein are for the treatment of acute or chronic pain. For example, the dosage form can be used to treat or prevent pain. Not specified, but cancer pain, central pain, labor pain, myocardial infarction pain, pancreatic pain, colic, postoperative pain To treat or prevent pain, including pain, headache, muscle pain, and pain associated with intensive care It can be used to

[0215] The dosage forms described herein can be administered to a subject to treat pain associated with inflammation or an inflammatory disease. It can also be used to treat or prevent. Pain can occur when inflammation of body tissues is present and can be caused by a local inflammatory response and / or a systemic The dosage form may be, but is not limited to, an inflammation associated with an inflammatory disease. Inflammatory diseases, including but not limited to organ transplant rejection; Reoxygenation injury resulting from organ transplantation, including kidney or liver transplantation (Grupp et al., Protection against Hypoxia-reoxygenation in the Absence of Poly (ADP-ribose) Syn thetase in Isolated Working Hearts, J.M. See Cell Cardiol. 31:297-303 (1999). including arthritis, rheumatoid arthritis, osteoarthritis and bone diseases associated with increased bone resorption Chronic inflammatory diseases of the joints; such as ileitis, ulcerative colitis, Barrett's syndrome, and Crohn's disease Inflammatory bowel disease; inflammatory lung diseases such as asthma, adult respiratory distress syndrome, and chronic obstructive airway disease Corneal dystrophy, trachoma, onchocerciasis, uveitis, sympathetic ophthalmia and endophthalmitis Inflammatory diseases of the eyes, including inflammatory diseases of the eyes; chronic inflammatory diseases of the gums, including gingivitis and periodontitis; tuberculosis; Hansen's disease uremic complications, inflammatory diseases of the kidneys, including glomerulonephritis and nephrosis; sclerodermatitis inflammatory diseases of the skin, including psoriasis and eczema; chronic demyelinating diseases of the nervous system, multiple sclerosis, AIDS S-related neurodegeneration and Alzheimer's disease, infectious meningitis, encephalomyelitis, Parkinson's disease, Han Central nervous system disorders, including Chinton's disease, amyotrophic lateral sclerosis, and viral or autoimmune encephalitis inflammatory diseases; autoimmune diseases, including type I and type II diabetes; Diabetic cataracts, glaucoma, retinopathy, kidney damage (microalbuminuria and progressive diabetic nephropathy) damage, etc.), polyneuropathy, mononeuropathy, autonomic neuropathy, gangrene of the foot, atherosclerotic coronary artery Cardiac artery disease, peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma, foot ulcers, joint disease and skin or mucosal complications (infections, shin rash, candida infections, or diabetic Diabetic complications, including necrobiosis lipoidica; immune complex vasculitis; systemic lupus erythematosus SLE; cardiomyopathy, ischemic heart disease, hypercholesterolemia, and atherosclerosis inflammatory diseases of the heart; also includes pre-eclampsia, chronic liver failure, brain and spinal cord trauma, and cancer and to treat or prevent pain associated with a variety of other diseases that may have a significant inflammatory component. The dosage forms described herein can also be used to treat, for example, gram-positive or or gram-negative shock, hemorrhagic or anaphylactic shock, or proinflammatory Cancer chemotherapy-induced shock in response to proinflammatory cytokines, e.g. Inflammation, which can be systemic inflammation of the body, exemplified by cytokine-related shock It can be used to treat or prevent pain associated with sexual disorders. Such shock can be induced, for example, by chemotherapy drugs administered as a treatment for cancer. .

[0216] Preparation method In some embodiments, the present invention provides a method for preparing the immediate release solid oral dosage forms disclosed herein. The present invention relates to a method for producing a pharmaceutical composition coated with an active agent composition and / or a delayed-release gelling agent composition. The collected spheroids or beads can be separated, for example, by rotor stratification or by top spraying. Therefore, by roller compaction, by bottom spray (e.g. Wurster coating) or by any conceivable combination of these methods. In certain embodiments, the active agent composition and / or the delayed release gelling agent composition are coated. The coated spheroids or beads are roller compacted, followed by crushing and sieving. It can be prepared by mixing.

[0217] In certain embodiments, a process for preparing an immediate release solid oral dosage form according to the present invention is The method includes (i) preparing a delayed-release gelling agent composition; (ii) preparing a delayed-release gelling agent composition; with an active pharmaceutical composition; and (iii) compressing the blend into tablets. In certain embodiments, the preparation of the delayed-release gelling agent composition comprises incorporating the gelling agent into an enteric coating. This may include performing a test.

[0218] For example, FIG. 1 shows a non-linear diagram for producing immediate release solid oral dosage forms by rotor layering. A limited process flow diagram is shown. Blocks 102 and 104 show The active beads or cores (e.g., microcrystalline cellulose spheres, MCC) are coated with a gelling agent ( Block 1 is coated with a mixture of 100% cellulose, 100% cellulose, 100% cellulose gum ... In 06, enteric materials (e.g., Eudragit® L30D-55) and plasticizers A coating dispersion containing a coating agent (e.g., PlasaACRYL™ HTP20) is mixed. The mixture is combined and sieved through a #30 mesh screen. Block 108 is The coating dispersion is then applied onto the coated gelling agent from block 104. rotor-layering to form a rotor-layered and enteric-coated delayed-release gelling agent composition. Blocks 110 to 126 are used to bind various components (e.g., naltrexone in block 112). HCl, MCC, sodium lauryl sulfate, and croscarmellose, Block 116 The rotor-layered and enteric-coated delayed-release gelling agent composition, block 120 Silicon dioxide, and magnesium stearate in block 124 and finally, at block 126, the blend from block 124 is compressed to form a compressed tablet. Block 1 shows the preparation of compressed naltrexone tablets by combining Block 1 and Block 2. The 26 compressed tablets may be subjected to dissolution and syringe penetration testing as described in the Examples below.

[0219] Another example of a non-limiting process for preparing an immediate release solid oral dosage form according to the present invention is shown in FIG. 2. FIG. 2 shows the preparation of an immediate release solid oral dosage form by the top spray granulation method. 2 shows a process flow diagram for manufacturing a fluororesin comprising: The gelatinized gel consists of an inert bead or nucleus (e.g., microcrystalline cellulose), a gelling agent (e.g., Ca rbopol 971 and xanthan gum), enteric dispersions in water (e.g., Eudragit (registered trademark) L30D-55) and a plasticizer dispersion in water (e.g., PlasaACRYL (trademark HTP20) was subjected to top spray granulation in a Vector fluid bed processor. Blocks 210 to 222 are used to identify various components (e.g., naltrexone in block 212). HCl, MCC, sodium lauryl sulfate, croscarmellose, and top spray retardant extended release gelling agent granules, colloidal silicon dioxide at block 216, and Magnesium stearate) and finally, block 222 is blended with block 220. Preparation of compressed naltrexone tablets by compressing the blend to form compressed tablets. The compressed tablet of block 222 is prepared by the same method as in block 2 as described in the examples below. 24 and can be subjected to dissolution and syringe penetration tests.

[0220] Another example of a non-limiting process for preparing an immediate release solid oral dosage form according to the present invention is shown in FIG. 3A-3B. FIG. 3A-3B shows the roller compaction / crushing / sieving and bottling process. To produce immediate release solid oral dosage forms by the muss spray (Wurster coating) method 3 shows a process flow diagram for the production of an inactive beads or nuclei (e.g., microcrystalline cellulose spheres, MCC), gelling agents (e.g., Carbopol 971 and Xanthan Gum), magnesium stearate, enteric dispersion in water (e.g., Eudragit® L30D-55) and plasticizer dispersions in water (e.g., For example, PlasaACRYL™ HTP20 is roller compacted, crushed, sieved, and Blocks 316 to 332 are made of various components ( Block 318 contains naltrexone HCl, MCC, sodium lauryl sulfate, and crosslinker. Carmellose, bottom sprayed and roller compacted delayed release gelation with Block 322 agent granules, colloidal silicon dioxide in block 326, and stearic acid in block 330 Magnesium) and finally block 332 blends the blend from block 330. Describes the preparation of compressed naltrexone tablets by compressing to form compressed tablets. The compressed tablets of block 332 are dissolved by block 334 as described in the Examples below. and may undergo needle penetration testing.

[0221] In certain embodiments, the process for preparing an immediate release solid oral dosage form comprises: (i) (ii) preparing one or more particles; and (iii) administering the one or more particles to a patient receiving an opioid analgesic. (iii) coating with an opioid analgesic drug composition; The method may include blending the gelled particle or particles with a delayed-release gelling agent composition. wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, and is free of, or substantially free of, sustained-release opioid analgesic compositions. (iv) compressing the blend into tablets.

[0222] In certain embodiments, the process for preparing an immediate release solid oral dosage form comprises: (i) (ii) preparing one or more delayed-release gelling agent particles; and The method may include coating delayed-release gelling agent particles with an opioid analgesic composition, In this case, the solid oral dosage form comprises an immediate release opioid analgesic composition, and the solid oral dosage form has a sustained release. The process is free of, or substantially free of, sustained-release opioid analgesic compositions. ii) compressing the one or more coated particles into a tablet. .

[0223] In certain embodiments, the process for preparing an immediate release solid oral dosage form comprises: (i) preparing one or more delayed-release gelling agent particles; and (ii) an opioid analgesic. Dispersing the composition and one or more delayed-release gelling agent particles in a matrix. wherein the solid oral dosage form comprises an immediate release opioid analgesic composition, The form is free or substantially free of sustained release opioid analgesic compositions. [Example]

[0224] The following examples are included to aid in the understanding of the present invention and, of course, are not intended to be limiting unless otherwise specified. and should not be construed as specifically limiting the invention as disclosed and claimed. Substitute all equivalents now known or hereafter developed that would be within the skill of the art. Such variations of the invention, including minor variations in formulation or experimental design, are within the scope of the present specification. It should be considered to fall within the scope of the present invention, which is incorporated herein by reference.

[0225] Example 1: Enteric-coated pellets prepared by rotor-layering process In this example, the gelling agent was added to microcrystalline cellulose (MCC) staples by rotor stratification. The pellets were then layered onto the enteric coating. Table 1: Rotor-stratified pellets [Table 1] * Used as a paint vehicle, evaporates during the process. # Eudragit® L 30D-55 is a 30% w / w dispersion, P lasACRYL™ HTP20 is a 20% w / w dispersion. Registered trademark)-Microcrystalline Cellulose Spheres Carbopol® 971P - Carboxypolymethylene or Carbomer Xantural® 75 - Xanthan Gum Eudragit® L30-55 - methacrylic acid-ethyl acrylate copolymer -(1:1) PlasACRYL™ HTP20—Water containing antiblocking agents, plasticizers, and stabilizers dispersion liquid

[0226] Gelling agent layering procedure Carbopol® 971P and Xantural® 75 Sieve the mixture through a #30 mesh screen and sieve it in a poly bag for 5 minutes. The Vivapur® spheres were mixed at room temperature to form a powder blend. The powder blend of Carbopol and Xanthan Gum was placed in the rotor insert of a fluidized bed apparatus. The powder blend was fed into the rotor using a K-Tron powder feeder. The powder layered pellet was formed by layering on the MCC sphere. The powder layering process parameters are listed in Table 2 below. Disclose to. Table 2: Process parameters for powder layering of gelling agents [Table 2] Enteric Coating Layering Procedure An aqueous dispersion of Eudragit® L30D-55 was mixed with a propeller stirrer. Add purified water and PlasACRYL™ HTP20 to Eudragit™ while stirring. The dispersion was prepared by adding at least 10 The dry powder layered pellets were enteric coated in a rotor process. The dispersion was coated to form coated pellets. The pellets were dried for 20 minutes to form rotor-layered pellets. The process parameters for enteric coating layering are disclosed in Table 3 below. Table 3: Process parameters for layering the enteric coating [Table 3]

[0227] Enteric-coated pellet samples were subjected to a 10% increase in enteric coating weight. , 15%, 20% and 30%.

[0228] Example 2: Naltrexone tablets containing rotor-layered pellets from Example 1 Two lots of naltrexone tablets were prepared, as summarized in Table 4 and Figure 1 below. , rotor-stratified pellets from Example 1 (Lot 2428-053A and Lot 2428 Lot 2428-053A was made using a gelling agent with a high content of (Carbopol 30 mg, Xanthan Gum 9 mg) and had a 10% enteric coating. Lot 2428-053B contains a low content of gelling agents (Carbopol 25 mg, Xanthan Gum) The enteric coating percentage was , Eudragit® L-30D-55 and PlasACRYL™ HT P20 was added to a gelling agent composition containing MCC spheres, carbopol, and xanthan gum. The calculation was based on the weight gain obtained from adding Table 4: Formulation of naltrexone tablets containing rotor-stratified pellets [Table 4] Avicel® PH102 - Microcrystalline Cellulose Ac-Di-Sol®-Croscarmellose Sodium Cab-O-Sil® - Colloidal Silicon Dioxide procedure: 1) Naltrexone HCl sieved through a #30 mesh screen for 5 minutes; Microcrystalline cellulose Avicel® PH102, sodium lauryl sulfate, Blend in roscarmellose sodium (Ac-Di-Sol®). 2) Add the rotor-layered pellets from Example 1 to the blend from Step 1 and mix for 10 minutes. Blend for a period of time. 3) Sieve the colloidal silicon dioxide through a #20 mesh screen, then Add to the blend from step 2 and blend for 5 minutes. 4) Sift the magnesium stearate through a #20 mesh screen and then Add to the blend from step 3 and blend for 2 minutes. 5) Compression: The mixture from step 4 is compressed in a tablet press according to the parameters in Table 5. Compress. Table 5: Compression process parameters [Table 5]

[0229] Example 3: Enteric-coated granules prepared by a top-spray fluid-bed granulation process Granules In this example, enteric coated granules of gelling agent were prepared by top spray granulation. Table 6: Gelling Agent Top Spray Enteric Granules [Table 6] * Used as a granulating agent, evaporates during processing. # Eudragit® L30D-55 is a 30% w / w dispersion, Pla sACRYL™ HTP20 is a 20% w / w dispersion.

[0230] Microcrystalline Cellulose PH101, Carbopol® 971P and Xant Sift together with ural® 75 (xanthan gum) through a #30 mesh screen. The mixture was collected, collected, and loaded into a fluid bed granulator bowl. TP20 was mixed with Eudragit® L30D- The dispersion was mixed for at least 10 minutes. The dispersion was sieved through a #30 mesh screen and subjected to the process parameters summarized in Table 7 below. The material was sprayed onto the bed using a top spray gun assembly according to the method described above. Table 7: Top spray granulation process parameters [Table 7] The obtained enteric coated granules were sieved through #60, #80, #100, and #200 mesh screens. During the process, some aggregates formed and were removed. The granules retained on the mesh screens (#100 mesh, #200 mesh) were also removed. The composite granules from the pan and the retained portion were used to make tablets. The percentage of granules retained after sieving is summarized in Table 8 below. Table 8: Particle size analysis [Table 8]

[0231] Example 4: Naltrexone tablets containing top-sprayed granules from Example 3 As summarized in Table 9 below and Figure 2, naltrexone tablets were prepared using the toppings from Example 3. Two lots (Lot 2428-048A and Lot 2428-048A) were prepared using plated granules. Lot 2428-048B) was made with a higher content of gelling agent ( Carbopol 30 mg, Xanthan gum 9 mg). Lot 2428-048B contains It had a lower content of gelling agents (Carbopol 25 mg, Xanthan gum 7.5 mg). . Table 9: Formulation for naltrexone tablets containing top-sprayed granules [Table 9] Avicel® PH 101 - Microcrystalline Cellulose procedure: 1) Naltrexone HCl, microcrystalline cellulose Avicel® PH102; Sodium lauryl sulfate, croscarmellose sodium (Ac-Di-Sol (registered trademark) The top-sprayed granules from Example 3 were sieved through a #30 mesh screen. Add and blend for 10 minutes. 2) Sieving the colloidal silicon dioxide through a #30 mesh screen, then Add to the blend from 1 and blend for 5 minutes. 3) Sift the magnesium stearate through a #60 mesh screen and add the Add to the blend and blend for 5 minutes. 4) Compression: The mixture from step 3 is compressed in a tablet press according to the parameters in Table 10. and compress it. Table 10: Compression process parameters [Table 10]

[0232] Example 5: Particles prepared by roller compaction In Examples 5 to 6, the gelling agent particles were roller compacted followed by Wurster coating ( The coating was prepared by bottom spray fluidized bed coating. Table 11: Roller compaction formulation [Table 11] Avicel® DG - Microcrystalline Cellulose procedure: 1) Avicel® DG, Carbopol® 971P, and Xan Turbulent® 75 was sieved through a #30 mesh screen and turbulent Blend using a blender for 10 minutes. 2) Sift the magnesium stearate through a #20 mesh screen and add the Add to the blend and then blend for 2 minutes. 3) Remove the block from step 2 according to the roller compaction parameters summarized in Table 12. The blend is used for roller compaction. Table 12: Roller Compaction Parameters [Table 12]

[0233] The resulting particles were analyzed and their particle size distribution, bulk density, and tapped density are shown in Table 13 below. To summarize. Table 13: Particle size distribution, bulk and tapped density [Table 13]

[0234] From the roller compaction test, it was found that the roller speed and auger speed were related to the particle size and density of the granules. As described in Example 6 below, the test Granules from 6 were coated with Eudragit® L30D-55 dispersion .

[0235] Example 6: Fluid Bed Coating (Bottom Spray) of Roller Compacted Granules In this example, the roller-compacted particles from Example 5 were mixed with water as summarized below. It was coated with Luster coating. Table 14: Wurster Coating Formulations [Table 14] * Used as a coating vehicle, evaporates during the process. # Eudragit® L30D-55 is a 30% w / w dispersion, PlasAC RYL™ HTP20 is a 20% w / w dispersion. procedure: 1) Sift the granules from Test 6 (Example 5) through a #30 and #40 mesh screen. do. 2) #4 for enteric coating with Eudragit® L30D-55 The retained fraction is separated through a 0 mesh screen. 3) Add purified water and P with stirring using a propeller stirrer for at least 10 minutes. lasACRYL™ HTP20 to Eudragit® L30D-55 By adding, a coating dispersion is prepared. 4) Pass the dispersion through a #30 mesh screen. 5) According to the Wurster coating parameters summarized in Table 15 below: Using the bottom spray Wurster insert in the Mini VFC, the dispersion was Spray onto the granules from step 1. Table 15: Wurster coating parameters [Table 15]

[0236] The coated granules were sieved through #20 mesh, #30 mesh and #40 mesh screens. The part above the #20 mesh was agglomerates and was discarded. The portions retained on the 0 mesh screen were combined and used to make the tablets of Example 7. Used.

[0237] Example 7: Naltrexone containing roller-compacted and bottom-sprayed granules of Example 6 tablet As summarized in Table 16 below and Figures 3A-3B, naltrexone tablets were prepared in the following manner. Two lots were prepared using roller-compacted and bottom-sprayed granules from Example 6. Lot 2428-069A and Lot 2428-069B). 9A had a high content of gelling agents (Carbopol 30 mg, Xanthan Gum 9 mg) Lot 2428-069B contains a low content of gelling agent (Carbopol 20 mg, Xanthan Gum) The product contained 6 mg of gum. Table 16: Naltrexone tablets containing roller-compacted and bottom-sprayed granules combination [Table 16] procedure: 1) Naltrexone HCl, Microcrystalline Cellulose Avicel® PH 102 , sodium lauryl sulfate, croscarmellose sodium (Ac-Di-Sol (registered ®) through a #30 mesh screen and blend for 5 minutes. 2) Add the roller-compacted and bottom-sprayed granules of Example 6 to the mixture from Step 1 and blend for 9 minutes. 3) Screen the colloidal silicon dioxide through a #20 mesh screen and add the sieve from step 2. Add to blend and blend for 2 minutes. 4) Sift the magnesium stearate through a #20 mesh screen and add the mixture from step 3. Add to the blend from above and blend for 2 minutes. 5) Compression: Compress the mixture from step 4 in a tablet press according to the parameters in Table 17. do. Table 17: Compression parameters [Table 17]

[0238] The tablets of Examples 2, 4 and 7 were subjected to dissolution and syringe penetration tests. Test Procedures and Results are summarized in Examples 8 and 9 and the corresponding figures.

[0239] Example 8: Needle penetration test The tablets of Examples 2, 4 and 7 were dissolved in 5 ml and 10 ml of tap water at room temperature. Tablets were tested for syringeability over a period of 10 minutes in whole and crushed form. The volume of inhalation (over 5 minutes) was recorded and the naltrexone HCl content was assessed. The data are summarized in Tables 18 to 23 and Figures 4 to 7. Table 18: Volume (ml) aspirated after dissolving tablets in tap water at room temperature (5th minute complete) Intact tablets (Figure 4) [Table 18]

[0240] The data in Table 18 are shown in Figure 4. Using the top spray fluid bed granules of Example 4 and in various volumes of tap water (5 ml and 10 ml) with and without stirring at room temperature. After dissolving an intact naltrexone HCl tablet in Ta.

[0241] The rotor-layered pellets of Example 2 were prepared by stirring and without stirring at room temperature. Dissolve intact naltrexone HCl tablets in tap water (5 ml and 10 ml). The volume aspirated after the gelling was lower for pellets with a higher gelling agent content. This is consistent with pellets with low gelling agent content and high enteric coating content. In comparison, the water content of pellets with high gelling agent content and low enteric coating content was This suggests a higher gelation rate in the tablets with higher gelling agent content. The volume of the large tablet was 6 ml, whereas that of the tablet with low gelling agent content was 6.9 ml.

[0242] For the roller compacted and bottom spray pellets of Example 7, the mixture was stirred at room temperature and Intact naltrexone in various volumes of tap water (5 ml and 10 ml) without stirring The volume aspirated after dissolving the HCl tablets was 0.01 for pellets with high gelling agent content. The maximum volume aspirated from the tablet with the higher gelling agent content was 6.7 ml. and 7.3 ml for tablets with low gelling agent content.

[0243] Roxicodone® (oxycodone HCl tablets) was used as a comparator. The maximum amount of roxicodone aspirated after dissolving intact roxicodone in tap water at room temperature was The volume was 9.9 ml. Various volumes of tap water ( Aspirated from intact Roxicodone after dissolution in 5 ml and 10 ml The volume absorbed after handling of the tablets prepared in Examples 2, 4, and 7 under the same operating conditions was greater than that absorbed after handling of the tablets prepared in Examples 2, 4, and 7 under the same operating conditions. was larger than the volume extracted. Table 19: Volume (ml) aspirated after dissolving tablets in tap water at room temperature for 5 minutes ) (Intact vs. Crushed Tablets - Figure 5) [Table 19] * Data is being evaluated The data in Table 19 are shown in Figure 5. Rotor Layering for Example 2 (Low Gelling Agent Content) The pellet was dissolved in 10 ml of tap water at room temperature (with and without stirring). The maximum volume aspirated from the intact tablet was 6.9 ml. The volume aspirated from the crushed tablets was lower after agitation.

[0244] For the roller compacted and bottom spray pellets of Example 7, the pellets were dissolved in 10 ml of tap water at room temperature. The volume aspirated for the dissolved intact tablets and crushed tablets was significantly higher for tablets with a high gelling agent content. After agitation, the tablet containing

[0245] Roxicodone (oxycodone HCl tablets) was used as a control. Dissolve intact and crushed Roxicodone in tap water. The maximum volume aspirated after stirring was 9.9 ml. Intact Roxicodone and crushed Roxicodone were dissolved in tap water. The volume aspirated from the codone was significantly higher than that of Example 2 (low gelling agent content) under the same operating conditions. The volume aspirated after dissolution of the tablets prepared in step 7 was larger than that of the tablets prepared in step 7. Table 20: Intake of intact tablets after dissolution in tap water at room temperature for 5 minutes Percentage assay of active drug in the collected liquid (Figure 6) [Table 20] * When a single number is listed in the table, it means that a single tablet was tested. do.

[0246] The data in Table 20 are shown in Figure 6. For the top spray fluid bed granulation of Example 4, The percentage of naloxone HCl drawn into the syringe is 2% of the labeled amount. The lower the value, the more pronounced this is.

[0247] For the rotor-layered pellets of Example 2, the performance in the syringe needle penetration test was 30% w / w Low gel containing Eudragit® L30D-55 enteric coated sample Compared to the gelling polymer content, the high gelling polymer content and Eudragit® The enteric coating of L30D-55 at 10% w / w was superior. Highest percentage of naltrexone HCl inhaled in rotor-stratified pellets containing naltrexone The level of gelling agent was 13.33% of the label claim, whereas the lower level of gelling agent was 20.06% of the label claim. This suggested significant gelation in water that prevented the drug from being syringeable.

[0248] For roller compaction and bottom spray pellets, the higher gelling agent lots It performed better than lots with lower gelling agent content. The maximum percentage of naltrexone HCl inhaled from the The amount of gelling agent was 36.5%.

[0249] Roxicodone (oxycodone HCl tablets) was used as a control. The maximum percentage of oxycodone administered was 44.2% of the labeled amount. Table 21: Activity in aspirated liquid after dissolving tablets in tap water at room temperature for 5 minutes Percentage Assay of Active Drug (Intact Tablets vs. Crushed Tablets - Figure 7) [Table 21]

[0250] The data in Table 21 are presented in Figure 7. When the tablets were crushed and dissolved in water, Rox The percentage of oxycodone injected from oxycodone (oxycodone HCl tablets) is , 90.6% of the label claim, but in the isolated gelling agent batch, it was significantly lower. .

[0251] Example 9: Dissolution Test The tablets of Examples 2, 4 and 7 were packed in a basket with a spring to a pressure of 0.1 N. The release of the active agent in HCl was tested. In vitro dissolution test of tablets according to Example 9 The experiment was carried out as follows: Tablets were tested in vitro in a USP Apparatus 1 (#4 900 ml of 0.1N HCl at 37.0 ± 0.5°C using a 0.0 mesh basket. When hydrated in dissolution media, the solids at the top of the basket or the bottom of the shaft To reduce the tendency of tablets to stick to the underside of the body, a retaining spring (passivated steel) A stainless steel 316 spring, 1.5 cm outer diameter and 2 cm length, is attached to the top of the basket (tablet The sampling time points were 5, 15, 30, 45, 60, and 90 minutes (or The results are summarized in Tables 22 to 25 and Figures 8 to 11. Table 22: 0.1N HCl in 900 ml using a basket with a spring Dissolution profile of (Figure 8) [Table 22]

[0252] The data in Table 22 are shown in Figure 8. Top spray fluid bed granulation approach (Example 4) The dissolution profile of the tablets prepared in Example 2 was evaluated using rotor stratification and roller pressure. This was slower than tablets made by the shrinkage approach (Example 7).

[0253] By the rotor stratification approach (Example 2) and the roller compaction approach (Example 7) Tablets made with sequestering gelling agents achieved over 90% drug release in 15 minutes. This was because the gelling agent was Eudragit® L30D-55 (greater than 5.5 The drug release is affected in acidic media because it is coated with a polymer that dissolves at low pH. This suggests that they will not be affected. Table 23: 0.1N HCl in 900 ml using a spring-loaded basket , Dissolution profile of tablets made with top-sprayed gelling agent granules (Example 4) Effect of hardness on [Table 23]

[0254] The data in Table 23 are shown in Figure 9. Top spray fluid bed granulation approach (Example 4) The dissolution profile of the tablets prepared in In addition, the hardness of the tablets with low amounts of gelling agent was slower than that of the tablets with hardness values ​​of 10 kP. The dissolution profile for the tablets from Example 4 was 0.01 for the tablets from Example 4 with a higher amount of gelling agent. It was later than expected.

[0255] Table 24: 0.1N HCl in 900 ml using a spring-loaded basket Dissolution profile of tablets made with rotor-layered gelling agent pellets (Example 2) Effect of hardness on the [Table 24]

[0256] The data in Table 24 are shown in Figure 10. The dissolution profiles of tablets made by the process (Example 2) were similar regardless of hardness. . Table 25: Roller compaction of gelling polymer, Wurster coated granules (Example 7 Effect of hardness on the dissolution profile of tablets made with [Table 25]

[0257] The data in Table 25 are shown in Figure 11. The dissolution profiles of tablets (Example 7) containing roller-compressed and wurster-coated granules of the gelling agent were the same regardless of hardness and regardless of the content of the gelling agent.

[0258] Summary of Examples 8 - 9 Table 26: Summary of Examples 8 - 9 and Tables 18 - 25 [Table 26]

[0259] Coatings of gelling agents that include Eudragit® L30D-55 and are incorporated into immediate-release dosage forms provide immediate release of the drug from the dosage form in the acidic pH (<pH 5.5) found in the stomach. When tablets are dissolved in water (up to 10 mL) for injection for IV abuse, the Eudragit coating dissolves in water having a pH above 5.5. Thus, the gelling agent is released and makes the solution viscous, preventing the passage of the syringe of the drug being abused. All three techniques used to coat the gelling agent with Eudragit® L30D-55 show a decrease in the amount of drug that can be injected when dissolved in water. In the top spray fluid bed granulation approach, the dissolution profile of the drug was slower.

[0260] In addition to preventing abuse via the intravenous route with the use of an isolated gelling agent, the incorporation of sodium lauryl sulfate, a nasal irritant, into the tablets of Examples 2, 4, and 7 prevents the nasal abuse of opioid formulations.

[0261] ​​​​​​​​​​​​For ease of explanation, method embodiments of the present disclosure are depicted and described as a series of acts. However, operations according to the present disclosure may be performed in various orders and / or simultaneously. and other operations not shown or described herein. Not all illustrated acts may be required to implement a methodology in accordance with the disclosed subject matter. In addition, those skilled in the art will appreciate that the method may alternatively be represented as a series of state diagrams. It will be understood and appreciated that the various aspects of the invention may be represented as interrelated states or events.

[0262] In the above description, specific materials, dimensions, processes, etc. are used in order to provide a thorough understanding of the present invention. It describes many specific details, such as specific characteristics, structures, materials, or The features may be combined in any suitable manner in one or more embodiments. The words "and" or "exemplary" are used herein to mean serving as an example, instance, or illustration. Any aspect described herein as an "example" or "exemplary" is intended to be illustrative and not restrictive. Any aspect or design is not necessarily to be construed as preferred or advantageous over other aspects or designs. Rather, the use of the words "example" or "exemplary" is intended to embody a concept. As used in this application, the term "or" means "and" or "also." is intended to mean an inclusive "or" rather than "is"; i.e., unless otherwise specified. Unless otherwise specified or clear from the context, "X includes A or B" It is intended to mean any natural inclusive permutation, i.e., X has X contains A; X contains B; or X contains both A and B, "X includes A or B" is satisfied in any of the above cases. References to "an embodiment," "a particular embodiment," or "one embodiment" in this specification A particular feature, structure, or characteristic described in connection with an embodiment may be present in at least one embodiment. Accordingly, the terms "embodiments" and "embodiments" in various places throughout this specification are intended to encompass all aspects of the present invention. Not all appearances of the phrases "a particular embodiment," "one embodiment," or "an embodiment" are to be construed as limiting the scope of the invention. , but do not relate to the same embodiment.

[0263] The present invention has been described with reference to specific exemplary embodiments thereof. Accordingly, the specification and drawings are to be regarded in an illustrative rather than a restrictive sense. Various modifications of the invention in addition to those shown and described herein will be apparent to those skilled in the art and are intended to fall within the scope of the appended claims. The present invention also includes the following aspects. <1> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, wherein the solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. <2> 2. The solid oral dosage form of claim 1, wherein the opioid analgesic is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, fentanyl, buprenorphine, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, and mixtures thereof. <3> 3. The solid oral dosage form according to any one of 1 to 2 above, comprising an analgesically effective amount of the opioid analgesic. <4> 3. The solid oral dosage form according to any one of 1 to 2 above, comprising about 0.1% to about 80% (w / w), or about 0.5% to about 30% (w / w), or about 1% to about 10% (w / w) of an opioid analgesic. <5> 5. The solid oral dosage form of any of 1 to 4 above, which releases at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the opioid analgesic within 30 minutes as measured by in vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml of 0.1 N HCl at room temperature. <6> 5. The solid oral dosage form of any of 1 to 4 above, which releases at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the opioid analgesic within 45 minutes as measured by in vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml of 0.1 N HCl at room temperature. <7> 5. The solid oral dosage form of any of 1 to 4 above, which releases at least about 80%, at least about 85%, at least about 90%, or at least about 95% of the opioid analgesic within 60 minutes as measured by in vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml of 0.1 N HCl at room temperature. <8> 8. The solid oral dosage form according to any one of 1 to 7 above, wherein the delayed-release gelling agent composition comprises a gelling agent and an enteric material. <9> 9. The solid oral dosage form of claim 8, wherein the gelling agent is selected from the group consisting of starch, starch derivatives, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, attapulgite, bentonite, dextrin, alginate, carrageenan, tragacanth gum, gum arabic, guar gum, xanthan gum, pectin, gelatin, kaolin, cross-linked polyacrylic acid, polyvinylpyrrolidone, polyethylene oxide, polyvinyl alcohol, and mixtures thereof. <10> 9. The solid oral dosage form of claim 8, wherein the gelling agent is selected from the group consisting of polyethylene oxide, xanthan gum, cross-linked polyacrylic acid, polysaccharides, and mixtures thereof. <11> 9. The solid oral dosage form of claim 8, wherein the gelling agent comprises a polymer. <12> 12. The solid oral dosage form of claim 11, wherein the polymer comprises a polysaccharide. <13> 13. The solid oral dosage form of claim 12, wherein the polysaccharide is a microbial polysaccharide. <14> 14. The solid oral dosage form of claim 13, wherein the microbial polysaccharide comprises xanthan gum. <15> 12. The solid oral dosage form of claim 11, wherein the polymer comprises an anionic polymer in a neutral pH aqueous solution. <16> 16. The solid oral dosage form of claim 15, wherein the anionic polymer comprises polyacrylic acid. <17> 17. The solid oral dosage form of claim 16, wherein the anionic polymer comprises a carbomer homopolymer. <18> 9. The solid oral dosage form of claim 8, wherein the gelling agent comprises xanthan gum and carbomer homopolymer. <19> 19. The solid oral dosage form according to any one of 1 to 18 above, comprising about 0.1% to about 50%, or about 0.5% to about 20%, or about 1% to about 10% (w / w) of a gelling agent. <20> 20. The solid oral dosage form according to any one of 1 to 19, wherein the viscosity of a solution obtained from the intact solid oral dosage form in about 0.5 ml to about 10 ml of water at room temperature after 5 minutes is about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more, wherein the viscosity is measured using a rotational viscometer. <21> 20. The solid oral dosage form according to any one of 1 to 19, wherein the viscosity of a solution obtained from the tampered solid oral dosage form in about 0.5 ml to about 10 ml of water at room temperature after 2 minutes is about 50 cP or more, about 75 cP or more, about 100 cP or more, or about 125 cP or more, wherein the viscosity is measured using a rotational viscometer. <22> 20. The solid oral dosage form according to any one of 1 to 19, wherein the viscosity of a solution obtained from the intact solid oral dosage form in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature at 5 minutes is less than about 50 cP, less than about 40 cP, less than about 30 cP, less than about 20 cP, less than about 10 cP, less than about 5 cP, or less than about 2 cP, wherein the viscosity is measured by a rotational viscometer. <23> 20. The solid oral dosage form according to any one of 1 to 19, wherein the viscosity of a solution obtained from the tampered solid oral dosage form in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature after 5 minutes is less than about 50 cP, less than about 40 cP, less than about 30 cP, less than about 20 cP, less than about 10 cP, less than about 5 cP, or less than about 2 cP, wherein the viscosity is measured by a rotational viscometer. <24> 20. The solid oral dosage form according to any one of 1 to 19 above, wherein the viscosity of a solution obtained from the intact solid oral dosage form in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature after 5 minutes is within about 30%, about 20%, about 10%, or about 5% of the viscosity of a solution obtained from the tampered solid oral dosage form in about 0.5 ml to about 10 ml of 0.1 N HCl at room temperature after 5 minutes, wherein the viscosity is measured by a rotational viscometer. <25> 20. The solid oral dosage form according to any one of claims 1 to 19, wherein the ratio of the viscosity of a solution obtained from the intact solid oral dosage form in about 5 ml of water at room temperature at 5 minutes to the viscosity of a solution obtained from the intact solid oral dosage form in about 5 ml of 0.1 N HCl at room temperature at 5 minutes is about 10:1 or more, about 15:1 or more, about 20:1 or more, about 25:1 or more, or about 30:1 or more, wherein the viscosity is measured by a rotational viscometer. <26> 26. The solid oral dosage form according to any one of claims 1 to 25, wherein the opioid analgesic composition is in the form of one or more particles. <27> 27. The solid oral dosage form of claim 26, wherein each opioid analgesic particle comprises the opioid analgesic coated on an inert core or the opioid analgesic dispersed in a matrix material. <28> 9. The solid oral dosage form of claim 8, wherein the delayed-release gelling agent composition is in the form of one or more particles. <29> 29. The solid oral dosage form of claim 28, wherein each delayed-release gelling agent particle comprises (i) the gelling agent coated with the enteric material, (ii) an inert core coated with the gelling agent and overcoated with the enteric material, or (iii) the gelling agent dispersed in a matrix material. <30> 30. The solid oral dosage form according to any one of claims 26 to 29, wherein the one or more opioid analgesic particles and the one or more delayed-release gelling agent particles are contained in a pharmaceutically acceptable capsule. <31> 30. The solid oral dosage form according to any one of claims 26 to 29, wherein the one or more opioid analgesic particles and the one or more delayed-release gelling agent particles are compressed into a tablet. <32> 30. The solid oral dosage form of claim 28 or 29, wherein the opioid analgesic composition is coated onto the one or more delayed-release gelling agent particles. <33> 30. The solid oral dosage form of claim 28 or 29, wherein the one or more delayed-release gelling agent particles are dispersed in a matrix comprising the opioid analgesic composition. <34> 34. The solid oral dosage form according to any one of claims 8 to 33, wherein the enteric material dissolves at a pH above about 5.5. <35> 34. The solid oral dosage form according to any one of 8 to 33 above, wherein the enteric material does not dissolve at a pH below about 5.5. <36> 34. The solid oral dosage form according to any one of claims 8 to 33, wherein the enteric material dissolves at a pH above about 5.5 and does not dissolve at a pH below about 5.5. <37> 34. The solid oral dosage form according to any one of 8 to 33 above, wherein the enteric material is selected from the group consisting of a cellulosic material, an acrylic acid polymer, a methacrylic acid polymer, and mixtures thereof. <38> 34. The solid oral dosage form according to any one of claims 8 to 33, wherein the enteric material is selected from the group consisting of methacrylic acid / methyl methacrylate, methacrylic acid / ethyl acrylate copolymer, methacrylic acid / methyl acrylate / methyl methacrylate copolymer, shellac, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose trimellitate, cellulose acetate phthalate, polyvinyl acetate phthalate, or a mixture thereof. <39> 30. A solid oral dosage form according to claim 28 or 29, wherein each particle comprises from about 10% to about 30% (w / w), or from about 12% to about 25% (w / w) of enteric material. <40> 39. The solid oral dosage form according to any one of 8 to 38 above, comprising about 0.1% to about 50% (w / w), about 1% to about 20% (w / w), or about 2% to about 15% (w / w) of an enteric material. <41> 41. The solid oral dosage form according to any one of 1 to 40 above, further comprising an aversive agent. <42> 42. The solid oral dosage form of claim 41, wherein the aversive agent is selected from the group consisting of an emetic, an antagonist, a bittering agent, an irritant, and mixtures thereof. <43> 43. The solid oral dosage form of claim 42, wherein the emetic agent is selected from the group consisting of methylcephalin, cephalin, emetine hydrochloride, psychotrin, O-methylpsychotrin, emethamine, ipecamine, hydroipecamine, ipecac acid, ipecac, and mixtures thereof. <44> 43. The solid oral dosage form of claim 42, wherein the antagonist is selected from the group consisting of naltrexone, naloxone, nalmefene, cyclazacine, levallorphan, pharmaceutically acceptable salts thereof, solvates thereof, prodrugs thereof, and combinations thereof. <45> 43. The solid oral dosage form of claim 42, wherein the aversive agent is a bittering agent selected from the group consisting of flavor oils, flavoring fragrances, oleoresins, plant extracts, leaf extracts, flower extracts, fruit extracts, sucrose derivatives, chlorosucrose derivatives, quinine sulfate, denatonium benzoate, and mixtures thereof. <46> 43. The solid oral dosage form of claim 42, wherein the aversive agent is a bittering agent selected from the group consisting of spearmint oil, peppermint oil, eucalyptus oil, nutmeg oil, allspice, mace, bitter almond oil, menthol, and mixtures thereof. <47> 43. The solid oral dosage form of claim 42, wherein the aversive agent is a bittering agent extracted from a fruit selected from the group consisting of lemon, orange, lime, grapefruit, and mixtures thereof. <48> 43. The solid oral dosage form of claim 42, wherein the aversive agent is an irritant selected from the group consisting of surfactants, capsaicin, capsaicin analogs, and mixtures thereof. <49> 49. The solid oral dosage form of claim 48, wherein the capsaicin analog is selected from the group consisting of resiniferatoxin, tiniatoxin, heptanoyl isobutyramide, heptanoyl guaiacylamide, isobutyramide, guaiacylamide, dihydrocapsaicin, homovanillyl octyl ester, nonanoyl vanillylamide, and mixtures thereof. <50> 49. The solid oral dosage form of claim 48, wherein the surfactant is selected from the group consisting of poloxamer, sorbitan monoester, glyceryl monooleate, sodium lauryl sulfate, or a combination thereof. <51> 51. The solid oral dosage form according to any one of 1 to 50 above, comprising about 0.1% to about 30% (w / w), or about 0.5% to about 20% (w / w), or about 1% to about 10% (w / w) of a stimulant. <52> 52. The solid oral dosage form according to any one of 1 to 51 above, further comprising a pharmaceutically acceptable excipient. <53> 53. The solid oral dosage form of claim 52, wherein the pharmaceutically acceptable excipient is selected from the group consisting of plasticizers, colorants, lubricants, fillers, thermal lubricants, antioxidants, buffers, disintegrants, binders, diluents, fluidization enhancers, anti-adherents, sweeteners, chelating agents, flavoring agents, surfactants, solubilizers, stabilizers, hydrophilic polymers, hydrophobic polymers, waxes, lipophilic substances, absorption enhancers, preservatives, absorbents, crosslinkers, bioadhesive polymers, pore formers, osmolality adjusters, polycarboxylic acids, or combinations thereof. <54> 54. The solid oral dosage form of claim 53, wherein the filler is selected from the group consisting of lactose, dextrose, mannitol, microcrystalline cellulose, and mixtures thereof. <55> 54. The solid oral dosage form of claim 53, wherein the fluidization enhancer comprises silicon dioxide. <56> 54. The solid oral dosage form of claim 53, wherein the lubricant comprises magnesium stearate. <57> 57. The solid oral dosage form according to any one of 1 to 56 above, comprising about 0.1% to about 99% (w / w), about 10% to about 80% (w / w), or about 15% to about 70% (w / w) of a pharmaceutically acceptable excipient. <58> 58. The solid oral dosage form of any of claims 1-57, wherein the delayed-release gelling agent composition comprises one or more of rotor-layered and enteric-coated pellets, top-sprayed granules, roller-compacted pellets, bottom-sprayed granules, or combinations thereof. <59> 59. A solid oral dosage form according to any one of 1 to 58 above, which is in the form of a unit dosage form. <60> 59. A solid oral dosage form according to any one of 1 to 58 above, which is in the form of multiple particles. <61> 60. A solid oral dosage form according to claim 59, in the form of a tablet. <62> 61. A solid oral dosage form as described in claim 60, wherein the plurality of particles are contained within a pharmaceutically acceptable capsule. <63> 63. The solid oral dosage form according to any one of 1 to 62 above, wherein the weight ratio of opioid analgesic to gelling agent is selected from the group of about 1:30 to about 30:1, or about 1:15 to about 15:1, or about 1:10 to about 10:1, or about 1:8 to about 8:1, or about 1:5 to about 5:1, or about 1:3 to about 3:1, or about 1:1.5 to about 1.5:1. <64> 64. The solid oral dosage form according to any one of 7 to 63 above, wherein the weight ratio of gelling agent to enteric substance is selected from the group consisting of about 1:30 to about 30:1, or about 1:15 to about 15:1, or about 1:10 to about 10:1, or about 1:8 to about 8:1, or about 1:3 to about 3:1, or about 1:1.5 to about 1.5:1. <65> 65. A solid oral dosage form according to any one of claims 1 to 64, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the intact solid oral dosage form is dissolved in 5 ml of a solvent with stirring at room temperature and the resulting solution is drawn up with an 18, 22, 25, or 27 gauge needle. <66> 65. The solid oral dosage form according to any one of claims 1 to 64, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the intact solid oral dosage form is dissolved in 10 ml of solvent with stirring at room temperature and the resulting solution is drawn up with an 18-, 22-, 25-, or 27-gauge needle. <67> 65. The solid oral dosage form of any of claims 1 to 64, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the intact solid oral dosage form is dissolved in 5 ml of solvent at room temperature without stirring and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <68> 65. The solid oral dosage form according to any one of claims 1 to 64, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the intact solid oral dosage form is dissolved in 10 ml of solvent at room temperature without stirring and the resulting solution is withdrawn with an 18, 22, 25, or 27 gauge needle. <69> 65. The solid oral dosage form according to any one of 1 to 64 above, wherein the recovery rate of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the crushed solid oral dosage form is dissolved in 5 ml of a solvent while stirring at room temperature and the resulting solution is aspirated with an 18-, 22-, 25-, or 27-gauge needle. <70> 65. The solid oral dosage form according to any one of 1 to 64 above, wherein the recovery rate of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the crushed solid oral dosage form is dissolved in 10 ml of a solvent while stirring at room temperature and the resulting solution is aspirated with an 18-, 22-, 25-, or 27-gauge needle. <71> 65. The solid oral dosage form according to any one of 1 to 64 above, wherein the recovery rate of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the crushed solid oral dosage form is dissolved in 5 ml of solvent at room temperature without stirring and the resulting solution is aspirated with an 18-, 22-, 25-, or 27-gauge needle. <72> 65. The solid oral dosage form according to any one of claims 1 to 64, wherein the recovery rate of the opioid analgesic is less than about 40%, less than about 30%, less than about 20%, less than about 10%, less than about 8%, less than about 6%, less than about 4%, or less than about 2%, based on a needle passage test in which the crushed solid oral dosage form is dissolved in 10 ml of solvent at room temperature without stirring and the resulting solution is aspirated with an 18-, 22-, 25-, or 27-gauge needle. <73> 73. The solid oral dosage form according to any one of claims 1 to 72, wherein the viscosity of said solid oral dosage form when mixed with about 0.5 ml to about 10 ml of water makes said opioid analgesic unsuitable for parenteral or intravenous administration. <74> 74. The solid oral dosage form according to any one of 1 to 73, wherein the delayed-release gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 5% to about 35% (w / w) of enteric material based on the total weight of the delayed-release gelling agent composition. <75> 74. The solid oral dosage form according to any one of 1 to 73, wherein the delayed-release gelling agent composition comprises rotor-layered, enteric-coated pellets comprising about 5% to about 15% (w / w) of enteric material based on the total weight of the delayed-release gelling agent composition. <76> 74. The solid oral dosage form according to any one of 1 to 73, wherein the delayed-release gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 15% to about 25% (w / w) of enteric material based on the total weight of the delayed-release gelling agent composition. <77> 74. The solid oral dosage form according to any one of 1 to 73, wherein the delayed-release gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 25% to about 35% (w / w) of enteric material based on the total weight of the delayed-release gelling agent composition. <78> 74. The solid oral dosage form according to any one of claims 1 to 73, wherein the delayed-release gelling agent composition comprises rotor layering and enteric-coated pellets comprising about 10% (w / w) of an enteric coating relative to the total weight of the delayed-release gelling agent composition. <79> 74. The solid oral dosage form according to any one of claims 1 to 73, wherein the delayed-release gelling agent composition comprises rotor layering and enteric-coated pellets comprising about 30% (w / w) of an enteric coating relative to the total weight of the delayed-release gelling agent composition. <80> 74. The solid oral dosage form according to any one of claims 1 to 73, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 90% to about 100% of the top-spray granules incorporated into the solid oral dosage form are retained in one or more of a 100 mesh screen, a 200 mesh screen, and a pan. <81> 81. The solid oral dosage form of claim 80, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 20% to about 50% of the top-spray granules incorporated into the solid oral dosage form are retained on a 100 mesh screen. <82> 81. The solid oral dosage form of claim 80, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 30% to about 45% of the top-spray granules incorporated into the solid oral dosage form are retained on a 100 mesh screen. <83> 83. The solid oral dosage form according to any one of claims 80 to 82, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 20% to about 50% of the top-spray granules incorporated into the solid oral dosage form are retained on a 200 mesh screen. <84> 83. The solid oral dosage form according to any one of claims 80 to 82, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 30% to about 45% of the top-spray granules incorporated into the solid oral dosage form are retained on a 200 mesh screen. <85> 85. The solid oral dosage form according to any one of claims 80 to 84, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 10% to about 30% of the top-spray granules incorporated into the solid oral dosage form are retained after sieving through a 200 mesh screen. <86> 85. The solid oral dosage form according to any one of claims 80 to 84, wherein the delayed-release gelling agent composition comprises top-spray granules, and about 15% to about 25% of the top-spray granules incorporated into the solid oral dosage form are retained after sieving through a 200 mesh screen. <87> 74. The solid oral dosage form according to any one of claims 1 to 73, wherein the delayed-release gelling agent composition comprises roller-compacted pellets having a bulk density in the range of about 0.4 g / ml to about 0.6 g / ml. <88> 74. The solid oral dosage form of any of claims 1 to 73, wherein the delayed-release gelling agent composition comprises roller-compacted pellets having a tap density in the range of about 0.55 g / ml to about 0.65 g / ml. <89> 89. A solid oral dosage form according to any one of 1 to 88 above, which is in the form of a compressed tablet. <90> 90. The solid oral dosage form according to claim 89, wherein the compressed tablet has a hardness of about 2 Kp to about 20 Kp. <91> 91. The solid oral dosage form according to claim 90, wherein the compressed tablet has a hardness of about 5 Kp to about 18 Kp. <92> 92. The solid oral dosage form according to any one of 1 to 91 above, having a disintegration time in water in the range of about 10 seconds to about 30 minutes. <93> 93. A solid oral dosage form according to claim 92, having a disintegration time in water in the range of about 1 minute to about 10 minutes. <94> 93. A solid oral dosage form according to claim 92, having a disintegration time in water in the range of about 10 seconds to about 2 minutes. <95> 95. The solid oral dosage form according to any one of 1 to 94 above, having a disintegration time in SGF in the range of about 10 seconds to about 30 minutes. <96> 96. A solid oral dosage form according to any of the above 95, having a disintegration time in SGF in the range of about 1 minute to about 10 minutes. <97> 96. A solid oral dosage form according to claim 95, having a disintegration time in SGF in the range of about 10 seconds to about 2 minutes. <98> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate-release form and a gelling agent composition in delayed-release form, wherein the gelling agent composition comprises a gelling agent and an enteric material coating the gelling agent, and wherein the solid oral dosage form releases at least about 85% of the opioid analgesic within 45 minutes as measured by in vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml of 0.1 N HCl at room temperature. <99> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises a gelling agent and an enteric material; and The solid oral dosage form, wherein the enteric material dissolves at a pH above about 5.5 and does not dissolve at a pH below about 5.5. <100> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 10% (w / w) of enteric material based on the total weight of the pellets; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 15% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 5 ml to about 10 ml of tap water at room temperature without stirring and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <101> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 10% (w / w) of enteric material based on the total weight of the pellets; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 5% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 5 ml to about 10 ml of tap water with stirring at room temperature and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <102> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 30% (w / w) of enteric material based on the total weight of the pellets; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 20% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 10 ml of tap water with or without stirring at room temperature and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <103> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 30% (w / w) of enteric material based on the total weight of the pellets; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 10% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 5 ml of tap water at room temperature without stirring and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <104> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 30% (w / w) of enteric material based on the total weight of the pellets; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 5% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 5 ml of tap water with stirring at room temperature and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <105> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises top spray granules; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 2% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 5 ml to about 10 ml of tap water at room temperature, with or without stirring, and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <106> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises roller-compacted and bottom-sprayed granules; The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 40%, less than about 30%, less than about 10%, or less than about 8% based on a needle passage test in which the intact solid oral dosage form is dissolved in about 5 ml to about 10 ml of tap water at room temperature with or without stirring and the resulting solution is withdrawn through an 18, 22, 25, or 27 gauge needle. <107> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises rotor-layered and enteric-coated pellets comprising about 30% (w / w) of enteric material based on the total weight of the pellets; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 15%, less than about 10%, or less than about 5%, based on a needle passage test in which the crushed solid oral dosage form is dissolved in about 10 ml of tap water with or without stirring at room temperature and the resulting solution is drawn up with an 18-, 22-, 25-, or 27-gauge needle. <108> 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, the solid oral dosage form is free or substantially free of an opioid analgesic composition in sustained release form; the gelling agent composition comprises roller-compacted and bottom-sprayed granules; and The solid oral dosage form, wherein the recovery of the opioid analgesic is less than about 30%, less than about 25%, or less than about 5%, based on a needle passage test in which the crushed solid oral dosage form is dissolved in about 10 ml of tap water with or without stirring at room temperature and the resulting solution is withdrawn through an 18-, 22-, 25-, or 27-gauge needle. <109> A method of treating a disease or condition comprising administering a solid oral dosage form as described in any of the preceding paragraphs. <110> A method for treating pain, comprising administering the solid oral dosage form according to any one of 1 to 108 above. <111> 1. A solid oral dosage form comprising an active agent composition in immediate release form and a gelling agent composition in delayed release form, wherein the solid oral dosage form is free of, or substantially free of, an active agent composition in sustained release form. <112> 112. The solid oral dosage form of claim 111, wherein the active agent is a drug selected from the group consisting of opioid agonists, tranquilizers, CNS depressants, CNS stimulants, sedative-hypnotics, and mixtures thereof. <113> 1. A process for preparing a solid oral dosage form, comprising: (i) preparing a delayed-release gelling agent composition; (ii) blending the delayed-release gelling agent composition with an active agent composition; and (iii) compressing the blend into a tablet. <114> 114. The process according to claim 113, wherein the preparing step comprises enteric coating the gelling agent. <115> 115. The process of claim 114, wherein said step of enteric coating is carried out by a method selected from the group consisting of rotor powder layering, fluid bed granulation, roller compaction, fluid bed coating, and combinations thereof. <116> 1. A process for preparing a solid oral dosage form, comprising: (i) preparing one or more particles; (ii) coating the one or more particles with an opioid analgesic composition; and (iii) blending the one or more particles coated with the opioid analgesic composition with a delayed-release gelling agent composition, wherein the solid oral dosage form comprises an opioid analgesic composition in immediate release form, and the solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form. <117> (iv) The process according to claim 116, further comprising compressing the blend into a tablet. <118> 1. A process for preparing a solid oral dosage form, comprising: (i) preparing one or more delayed-release gelling agent composition particles; and (ii) coating the one or more delayed-release gelling agent particles with an opioid analgesic composition, wherein the solid oral dosage form comprises an opioid analgesic in immediate-release form, and the solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained-release form. <119> (iii) The process of claim 118, further comprising compressing the one or more coated particles into a tablet. <120> 1. A process for preparing a solid oral dosage form, comprising: (i) preparing one or more delayed-release gelling agent particles; and (ii) dispersing an opioid analgesic composition and the one or more delayed-release gelling agent particles in a matrix, wherein the solid oral dosage form comprises an opioid analgesic composition in immediate release form, and the solid oral dosage form is free of, or substantially free of, an opioid analgesic composition in sustained release form.

Claims

1. 1. A solid oral dosage form comprising an opioid analgesic composition in immediate release form and a gelling agent composition in delayed release form, 1. A solid oral dosage form comprising: a solid oral dosage form that is a tablet and is free of or substantially free of an opioid analgesic composition in sustained release form; a gelling agent composition in delayed release form that is free of the opioid analgesic composition; a gelling agent composition in delayed release form that is present in one or more particles and comprises 10% to 30% (w / w) of a gelling agent and an enteric material, the enteric material dissolving at a pH greater than 5.5 and insoluble at a pH less than 5.5; each delayed-release gelling agent particle comprising an inert core coated with the gelling agent and overcoated with the enteric material; and a ratio of the viscosity of a solution obtained from the intact solid oral dosage form in 5 ml of water at room temperature after 5 minutes to the viscosity of a solution obtained from the intact solid oral dosage form in 5 ml of 0.1 N HCl at room temperature after 5 minutes is 10:1 or greater, wherein the viscosity is measured by a rotational viscometer and the weight ratio of the gelling agent to the enteric material is 1:3 to 3:

1.

2. 2. The solid oral formulation of claim 1, wherein the opioid analgesic is selected from the group consisting of morphine, hydromorphone, hydrocodone, oxycodone, codeine, levorphanol, meperidine, dihydrocodeine, dihydromorphine, oxymorphone, fentanyl, buprenorphine, pharmaceutically acceptable salts thereof, solvates thereof, and mixtures thereof.

3. 3. The solid oral dosage form of claim 1 or 2, comprising 0.1% to 80% (w / w) of an opioid analgesic.

4. 4. The solid oral dosage form of any one of claims 1 to 3, wherein the solid oral dosage form releases at least about 80% of the opioid analgesic within 30 minutes as measured by in vitro dissolution in a USP Apparatus 1 (#40 mesh basket) in 900 ml of 0.1 N HCl at room temperature.

5. 5. The solid oral formulation of claim 1, wherein the gelling agent is selected from the group consisting of starch, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, attapulgite, bentonite, dextrin, alginate, carrageenan, tragacanth gum, arabic gum, guar gum, xanthan gum, pectin, gelatin, kaolin, cross-linked polyacrylic acid, polyvinylpyrrolidone, polyethylene oxide, polyvinyl alcohol, and mixtures thereof.

6. 6. The solid oral dosage form of any one of claims 1 to 5, wherein the gelling agent is selected from the group consisting of polyethylene oxide, xanthan gum, cross-linked polyacrylic acid, polysaccharides, and mixtures thereof.

7. 7. The solid oral dosage form of any one of claims 1 to 6, wherein the gelling agent comprises xanthan gum and carbomer homopolymer.

8. A solid oral formulation according to any one of claims 1 to 7, comprising 0.1% to 50% of a gelling agent (w / w).

9. 9. The solid oral formulation according to claim 1, wherein the viscosity of a solution obtained from the intact solid oral formulation in 0.5 ml to 10 ml of water at room temperature after 5 minutes is 50 cP or more, wherein the viscosity is measured by a rotational viscometer.

10. The solid oral formulation of claim 1, wherein the delayed-release gelling agent particles are made by a top-spray fluidized bed granulation approach.

11. 11. The solid oral dosage form of any one of claims 1 to 10, wherein the opioid analgesic composition is in the form of one or more particles.

12. The solid oral formulation of claim 1, wherein the enteric material comprises a methacrylic acid / ethyl acrylate copolymer.

13. A solid oral formulation according to any one of claims 1 to 12 for the treatment of pain.

14. A method for preparing the solid oral formulation of claim 11, comprising: (i) preparing one or more particles; (ii) coating the one or more particles with the opioid analgesic composition; and (iii) blending the one or more particles coated with the opioid analgesic composition with the delayed-release gelling agent composition.

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